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BackgroundLoco-regional recurrences (LRR) following breast-conserving surgery (BCS) remain a heterogeneous class of disease that has significant variation in its biological behavior and prognosis.MethodsTo delineate the spatiotemporal patterns of LRR after BCS, we analyzed the data of 4325 patients treated with BCS from 2006 to 2016. Clinico-pathological and treatment specific factors were analyzed using the Cox proportional hazards model to identify factors predictive for LRR events. Recurrence patterns were scrutinized based on recurrence type and recurrence-free interval (RFI). Annual recurrence rates (ARR) were compared according to recurrence type and molecular subtype.ResultsWith a median follow-up of 66 months, 120 (2.8%) LRRs were recorded as the first site of failure. Age, pathologic stage, and molecular subtype were identified as predictors of LRR. The major recurrence type was ipsilateral breast tumor recurrence, which mainly (83.6%) occurred ≤5y post surgery. In the overall population, ARR curves showed that relapse peaked in the first 2.5 years. Patients with regional nodal recurrence, shorter RFI, and synchronous distant metastasis were associated with a poorer prognosis. HER2-positive disease had a higher rate of LRR events, more likely to have in-breast recurrence, and had an earlier relapse peak in the first 2 years after surgery.ConclusionsLRR risk following BCS is generally low in Chinese ethnicity. Different recurrence patterns after BCS were related to distinct clinical outcomes. Management of LRR should be largely individualized and tailored to the extent of disease, the molecular profile of the recurrence, and to baseline clinical variables.

Purpose Regulatory T cells (Tregs) heavily infiltrate triple-negative breast cancer (TNBC), and their accumulation is affected by the metabolic reprogramming in cancer cells. In the present study, we sought to identify cancer cell-intrinsic metabolic modulators correlating with Tregs infiltration in TNBC.Experimental design Using the RNA-sequencing data from our institute (n=360) and the Molecular Taxonomy of Breast Cancer International Consortium TNBC cohort (n=320), we calculated the abundance of Tregs in each sample and evaluated the correlation between gene expression levels and Tregs infiltration. Then, in vivo and in vitro experiments were performed to verify the correlation and explore the underlying mechanism.Results We revealed that GTP cyclohydrolase 1 (GCH1) expression was positively correlated with Tregs infiltration and high GCH1 expression was associated with reduced overall survival in TNBC. In vivo and in vitro experiments showed that GCH1 increased Tregs infiltration, decreased apoptosis, and elevated the programmed cell death-1 (PD-1)-positive fraction. Metabolomics analysis indicated that GCH1 overexpression reprogrammed tryptophan metabolism, resulting in L-5-hydroxytryptophan (5-HTP) accumulation in the cytoplasm accompanied by kynurenine accumulation and tryptophan reduction in the supernatant. Subsequently, aryl hydrocarbon receptor, activated by 5-HTP, bound to the promoter of indoleamine 2,3-dioxygenase 1 (IDO1) and thus enhanced the transcription of IDO1. Furthermore, the inhibition of GCH1 by 2,4-diamino-6-hydroxypyrimidine (DAHP) decreased IDO1 expression, attenuated tumor growth, and enhanced the tumor response to PD-1 blockade immunotherapy.Conclusions Tumor-cell-intrinsic GCH1 induced immunosuppression through metabolic reprogramming and IDO1 upregulation in TNBC. Inhibition of GCH1 by DAHP serves as a potential immunometabolic strategy in TNBC.

Background Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer and lacks definite treatment targets. Tumor immune microenvironment (TIME) heterogeneity has a profound impact on the immunotherapy response. Tumors with non-inflamed TIME derive limited benefit from immunotherapy. However, what drives the formation of the non-inflamed TIME in TNBC remains unclear.Methods Using our multiomics database of TNBC, we conducted an analysis to explore the key genomic events driving the formation of the non-inflamed TIME in TNBC. In vitro and in vivo studies further revealed potential mechanisms and the efficacy of combination treatment with immunotherapy.Results With transcriptomic and genomic data, we systematically analyzed the TIME of TNBC and revealed that the classical basal-like subtype of TNBC consisted of two distinct microenvironment phenotypes, defined as the ‘inflamed’ and ‘non-inflamed’ subtypes. We performed further screening and demonstrated that MYC amplification and overexpression led to low immune infiltration and cytolytic activity in TIME. Mechanistically, MYC bound to DNMT1 promoter and activated DNMT1 transcription in TNBC cells, thus suppressing the Cyclic GMP-AMP synthase (cGAS)-STING pathway via an epigenetic regulatory way. In MYC-overexpressing TNBC, decitabine, an Food and Drug Administration (FDA)-approved DNA methyltransferase inhibitor, converted tumors from non-inflamed to inflamed tumors by enhancing T cell infiltration. Furthermore, the combination of decitabine with programmed cell death protein 1 (PD-1) inhibitor reversed T cell exhaustion and improved T cell function in mouse models, which elicited potent antitumor activity in MYC-overexpressing TNBC.Conclusions Our work elucidates that the classic oncogene MYC induces immune evasion by repressing innate immunity. Furthermore, we provide a rationale for combining DNA methyltransferase inhibition with immunotherapy for the treatment of MYC-overexpressing TNBC.

Background: De-escalating anthracycline is gaining popularity for breast cancer patients. We aim to evaluate the non-inferiority of an anthracycline-free or short-term regimen to the standard anthracycline-based regimen for operable patients with human epidermal growth factor receptor 2 (HER2)-negative breast cancer. Methods: It is a prospective, open-label, phase 3, randomized non-inferiority trial from June 1, 2010 to June 1, 2017. Follow-up had been kept until July 2019. This trial was conducted at Fudan University Shanghai Cancer Center. Patients with pT1–3N+ or pT2–3N0 but high-risk (grade II/III, lymphovascular invasion, ≤35 years of age or hormone-receptor negative) HER2-negative operable breast cancer were eligible and stratified by age, pathological tumour stage, pathological node status and hormone-receptor status. Patients were randomized to 6 cycles of docetaxel and cyclophosphamide (TC, n = 524), 3 cycles of cyclophosphamide/epirubicin/fluorouracil followed by 3 cycles of docetaxel (CEF-T, n = 523) or epirubicin and cyclophosphamide for 4 cycles followed by paclitaxel for 12 weeks (EC-P, n = 524) as the intention-to-treat population. Of these patients, 94% completed allocated therapy. Difference in disease-free survival (DFS) compared to EC-P. The prespecified non-inferiority margin was 4.5%, corresponding to the hazard ratio (HR) of 1.44 (one-sided α = 0.05), with an assumed 5-year DFS of 89% for EC-P. Findings: Included in the intention-to-treat population were 1571 patients (median [IQR] age, 50 [45–57] years; 92% estrogen receptor [ER]-positive; 59% pN+). Through a median follow-up of 5.5 years, HR for TC versus EC-P was 1.05 (5-year DFS: 85.0% vs. 85.9%; 90% confidence interval [CI]: 0.79–1.39, non-inferior P = 0.048) and for CEF-T versus EC-P, 0.99 (5-year DFS: 85.1% vs. 85.9%; 90% CI: 0.75–1.30, non-inferior P = 0.045). Grade 3 or 4 adverse events for TC included rash (3.9%) and peripheral neuropathy (2.8%) and for CEF-T and EC-P diarrhea and nausea/vomiting were predominant. Results of per-protocol analyses were similar. Interpretation: Both TC and CEF-T are non-inferior adjuvant regimen to EC-P mainly in patients with ER+HER2- breast cancer. TC is a safe regimen that avoids anthracycline-related side effects. Funding: This work was supported by grants from the National Natural Science Foundation of China (Grants 81672600, 81722032, 82072916, and 91959207), the 2018 Shanghai Youth Excellent Academic Leader, the Fudan ZHUOSHI Project, the Municipal Project for Developing Emerging and Frontier Technology in Shanghai Hospitals (grant SHDC12010116), the Cooperation Project of Conquering Major Diseases in the Shanghai Municipality Health System (grant 2013ZYJB0302), the Innovation Team of the Ministry of Education (grant IRT1223), and the Shanghai Key Laboratory of Breast Cancer (grant 12DZ2260100) and the National Cancer Institute (grant P30 CA16058).

Abstract BRCA1, a multifunctional protein with an important role in DNA double‐strand break repair by homologous recombination (HR), is subjected to ubiquitin‐dependent degradation. To date, several E3 ubiquitin ligases have been identified to govern BRCA1 stability, but the deubiquitinase that counteracts its turnover remains undefined. In this study, we report that the ubiquitin‐specific protease 9X (USP9X) is a bona fide deubiquitinase for BRCA1 in human cancer cells. Reciprocal immunoprecipitation assays demonstrated that USP9X interacted with BRCA1. Depletion of USP9X by short interfering RNAs or inhibition of USP9X by the small‐molecular inhibitor WP1130 significantly reduced BRCA1 protein abundance, without affecting its mRNA levels. In contrast, overexpression of wild‐type USP9X, but not its deubiquitinase activity‐defective mutant (C1566S), resulted in an upregulation of BRCA1 protein levels. Moreover, USP9X depletion reduced the half‐life of BRCA1, accompanied by an increase in its ubiquitination. HR assays showed that knockdown of USP9X significantly reduced HR efficiency, which was partially rescued by reintroduction of BRCA1 into USP9X‐depleted cells. In support of these findings, USP9X knockdown significantly enhanced sensitivity to PARP inhibitor Olaparib and methyl methanesulfonate (MMS). Collectively, these results establish USP9X as a deubiquitinase for BRCA1 and reveal a previously unrecognized role of USP9X in the regulation of HR repair and the sensitivity of cancer cells to DNA‐damaging agents.

Abstract Background Endocrine therapy is the preferred treatment for patients with hormone receptor ‐positive metastatic breast cancer (MBC). While visceral metastasis is a negative prognostic factor, few studies have distinguished between the prognoses of patients with metastases at different visceral sites. Patients and methods In total, 398 patients receiving fulvestrant 500 mg at a single center over a 6‐year period were analyzed. Logistic regression models were used to identify the prognostic factors associated with progression‐free survival (PFS). Kaplan‐Meier analysis was used to compare the PFS of patients with lung and liver metastases. Results Baseline visceral metastases were present in 233 patients, including 138 with lungw/o liver metastases (lung metastases without liver involvement), 51 with liverw/o lung metastases (liver metastases without lung involvement) and 41 with lung and liver metastases. The median PFS was 6.8 months (5.6 and 9.2 months for visceral and nonvisceral metastases, respectively, P = .028). PFS was longer in patients with lungw/o liver metastases than in those with liverw/o lung metastases or lung and liver metastases (9.6, 3.7 and 3.2 months, respectively, P

Abstract Background Enhanced glycolysis in tumors, known as the Warburg effect, provides the metabolic basis of enhanced cancer cell proliferation and metastasis. The Warburg pathway enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) is a newly identified key kinase that regulates transcriptional reprogramming and cell proliferation. Here we show the prognostic value of PFKFB4 expression in patients with operable breast cancer. Methods PFKFB4 expression was evaluated by immunohistochemistry in surgical specimens retrospectively collected from 200 patients with histologically proven invasive ductal breast cancer. Kaplan–Meier survival analysis and Cox regression analysis were performed to assess the prognostic significance of PFKFB4 expression. Results Kaplan–Meier survival analysis revealed that breast cancer patients with high PFKFB4 expression demonstrated unfavorable disease-free survival (p = 0.008) and overall survival (p = 0.002). PFKFB4 had an hazard ratio (HR) of 7.38 (95% CI 1.69–32.3; p = 0.008) in univariate Cox analysis and retained prognostic power (HR 7.44, 95% CI 1.67–33.2; p = 0.009) when adjusted by tumor size, lymph node status, grade, estrogen receptor status, human epidermal growth factor receptor 2 status and subtype, which indicated PFKFB4 was an independent prognostic factor in breast cancer. Conclusions Together, our findings establish the prognostic value of metabolic enzyme PFKFB4 in patients with operable breast cancer.

INTRODUCTION: The objective of current study was to develop and validate comprehensive nomograms for predicting the survival of young women with breast cancer. METHODS: Women aged

Background and PurposeAlthough tumor size and nodal status are the most important prognostic factors, it is believed that nodal status outperforms tumor size as a prognostic factor. In particular, when patients have a nodal stage greater than N2 (more than nine positive lymph nodes), it is well accepted that tumor size does not retain its prognostic value. Even in the newest American Joint Committee on Cancer (AJCC) prognostic staging system, which includes molecular subtype as an important prognostic factor, T1-3N2 patients are categorized as the same population. The same is true for T1-4N3 patients. Moreover, some physicians have speculated that for tumors staged N2 or greater, the smaller the tumor is, the more aggressive the tumor. Thus, this study aims to investigate the prognostic value of tumor stage (T stage) in patients with extensive nodal involvement and to compare the survival of T4N × M0 and T × N3M0.Patients and MethodsFemale breast cancer patients with nine or more positive lymph nodes or with T4 tumors were identified in the SEER registry between 2010 and 2015. The effect of T stage on breast cancer-specific survival (BCSS) was assessed using the Kaplan–Meier survival curve method and risk-adjusted Cox proportional hazard regression modeling. Survival comparison of T4NxM0 and TxN3M0 patients was also achieved using the Kaplan–Meier survival curve method and risk-adjusted Cox proportional hazard regression model.ResultsOverall, 21,696 women with N2-3 tumors were included from 284,073 patients.T stage, nodal stage (N stage), ER, PR, HER2 and grade were all independent prognostic factors (p

Abstract Pregnancy‐specific glycoprotein 9 (PSG9) is a placental glycoprotein essential for the maintenance of normal gestation in mammals. Bioinformatics analysis of multiple publicly available datasets revealed aberrant PSG9 expression in breast tumors, but its functional and mechanistic role in breast cancer remains unexplored. Here, we report that PSG9 expression levels were elevated in tumor tissues and plasma specimens from breast cancer patients, and were associated with poor prognosis. Gain‐ or loss‐of‐function studies demonstrated that PSG9 promoted breast cancer cell proliferation, migration, and invasionin vitro, and enhanced tumor growth and lung colonization in vivo. Mechanistically, transforming growth factor‐β1 (TGF‐β1) transcriptionally activated PSG9 expression through enhancing the enrichment of Smad3 and Smad4 onto PSG9 promoter regions containing two putative Smad‐binding elements (SBEs). Mutation of both SBEs in the PSG9 promoter, or knockdown of TGF‐β receptor 1 (TGFBR1), TGFBR2, Smad3, or Smad4 impaired the ability of TGF‐β1 to induce PSG9 expression. Consequently, PSG9 contributed to TGF‐β1‐induced epithelial‐mesenchymal transition (EMT) and breast cancer cell migration and invasion. Moreover, PSG9 enhanced the stability of Smad2, Smad3, and Smad4 proteins by blocking their proteasomal degradation, and regulated the expression of TGF‐β1 target genes involved in EMT and breast cancer progression, thus further amplifying the canonical TGF‐β/Smad signaling in breast cancer cells. Collectively, these findings establish PSG9 as a novel player in breast cancer progressionvia hijacking the canonical TGF‐β/Smad signaling, and identify PSG9 as a potential plasma biomarker for the early detection of breast cancer.

Background: Data on burden and changing trends of breast cancer are of value for policymaking. We aimed to determine the pattern of breast cancer incidence, mortality, and disability-adjusted life-years (DALYs), as well as temporal trends, from 1990 to 2017.Methods: We collected detailed information on breast cancer between 1990 and 2017 using the results of the Global Burden of Disease study. The number of incident cases, deaths, and DALYs attributable to breast cancer are reported as well as age-standardized rates. Estimated annual percentage changes (EAPCs) in age-standardized rates were calculated to quantify the temporal trends. Moreover, the attributable burden to breast cancer risk factors was also estimated.Results: There were 1,960,682 incident cases and 611,625 deaths of breast cancer globally in 2017, contributing to 17,708,600 DALYs. The age-standardized incidence rates (ASIRs) increased between 1990 and 2017, while the age-standardized mortality rates and DALY rates decreased. The corresponding EAPCs were 0.41, −0.62, and −0.56, respectively. These trends were heterogeneous across regions and countries. The increase in the ASIRs was more prominent in countries with a low sociodemographic index. The percentages of breast cancer deaths due to alcohol use and tobacco were decreasing, while deaths due to high body mass index and high fasting plasma glucose were increasing.Conclusion: Breast cancer remained a major public health concern globally. The trends of incidence, mortality, and DALYs were heterogeneous across regions and countries, suggesting that the allocation of appropriate health care resources for breast cancer should be considered at the national scale and even at the subnational scale.

Goals: BRCA1/2 mutations are associated with bilateral breast cancer. The extent of concordance between synchronous bilateral breast cancer (SBBC) tumors with respect to hormone receptor expression and BRCA1/2 mutations is unknown. We investigated the distribution of BRCA1/2 mutations and bilateral estrogen receptor (ER) status in SBBC.Methods: A retrospective analysis was performed on 15,337 patients with primary breast cancer who underwent surgical treatment at the Fudan University Shanghai Cancer Center between 2007 and 2014. We included 163 patients with synchronous bilateral breast cancer who had germline BRCA1/2 mutations testing. BRCA1/2 pathogenic/likely pathogenic mutations and other clinicopathological characteristics were studied in further analyses.Results: Patients with SBBC developed breast cancer at an older age and had a higher rate of ER positivity than patients with UBC (p < 0.001, separately). In contrast, 14.1% of SBBC patients had carcinomas with a lobular component in either breast based on pathological reports (p < 0.001). Twelve patients had BRCA1 mutations, and 14 patients had BRCA2 mutations, while no patients had mutations in both genes. The BRCA1/2 mutation rate was higher in younger patients (23.4 vs. 11.1%, p = 0.036). SBBC patients with a family history of breast cancer or bilateral ER-negative disease had a higher frequency of BRCA1/2 mutations than the cohort without a history of these conditions. SBBC with a bilateral ER-discordant status had a very low frequency of BRCA1/2 mutations (5.6%). Patients with an ER-positive (concordant or discordant) status had better 3-year disease-free survival than patients with a concordant ER-negative status (HR = 0.324, 95% CI: 0.126–0.837, P = 0.020). However, the outcomes were similar during long-term follow-up. Pathological lymph node stage was the only prognostic factor for SBBC in both univariate and multivariate Cox analyses.Conclusions: Our study shows that Chinese women with SBBC have different characteristics from their UBC counterparts. SBBC patients with a younger age, family history of breast cancer, or bilateral ER-negative disease are more likely to have BRCA1/2 mutations. SBBC patients with a concordant ER-negative status had worse early outcomes. Our results suggest that there may be additional factors underlying the tumor biology and genetics of SBBC.

Abstract Breast tumor initiating cells (BTICs) with ALDH+CD24−CD44+ phenotype are the most tumorigenic and invasive cell population in breast cancer. However, the molecular mechanisms are still unclear. Here, it is found that a negative immune regulator interleukin‐1 receptor type 2 (IL1R2) is upregulated in breast cancer (BC) tissues and especially in BTICs. BC patients with high IL1R2 expression have a poorer overall survival and relapse‐free survival. High IL1R2 promotes BTIC self‐renewal and BC cell proliferation and invasion. Mechanistically, IL1R2 is activated by IL1β, as demonstrated by the fact that IL1β induces the release of IL1R2 intracellular domain (icd‐IL1R2) and icd‐IL1R2 then interacts with the deubiquitinase USP15 at the UBL2 domain and promotes its activity, which finally induces BMI1 deubiquitination at lysine 81 and stabilizes BMI1 protein. In addition, IL1R2 neutralizing antibody can suppress the protein expression of both IL1R2 and BMI1, and significantly abrogates the promoting effect of IL1R2 on BTIC self‐renewal and BC cell growth both in vitro and in vivo. The current results indicate that blocking IL1R2 with neutralizing antibody provides a therapeutic approach to inhibit BC progression by targeting BTICs.

Abstract Duffy antigen receptor for chemokine (DARC) and CCBP2, the two members of chemokine decoy receptor family, restrain cell proliferation and invasion through sequestrating cytotoxic chemokines. Our previous research clarified two functional nonsynonymous single nucleotide polymorphisms (SNPs): rs12075 in DARC and rs2228468 in CCBP2 were significantly correlated with lymph node metastasis. However, the role of their genetic variations on survival of breast cancer remains unclear. In the present study, rs12075 in DARC and rs2228468 in CCBP2 were genotyped in 806 patients with primary breast cancer. The endpoint was recurrence‐free survival (RFS). Cox regression model was used to explore the association between SNPs and patients’ survival. The results revealed that participants with GG genotype in rs12075 appeared a higher recurrence risk compared with AG/AA genotype after adjustment with clinical parameters including lymph node status (AG+AA vs GG: hazard ratio [HR] = 0.54, 95% confidence interval [CI], 0.31‐0.93, P = 0.027). Furthermore, subgroup analysis revealed that GG genotype frequency of rs12075 had a positive correlation with RFS compared with AG/AA genotype (AG+AA vs GG: HR = 0.22, 95% CI, 0.05‐0.91, P = 0.021) in triple‐negative breast cancer (TNBC) subtype but not in other subtypes. No significant association between the genotypic variants and relapse risk was found in rs2228468 (AC+AA vs CC: HR = 0.80, 95% CI, 0.56‐1.14, P = 0.222). There was also no significant difference in survival among rs2228468 polymorphism in any subtypes. Our study suggested that rs12075 could be served as a key predictive factor of recurrence risk in breast cancer, especially for TNBC subtype. Further researches to monitor SNPs will provide further opportunities to determine clinical prognosis.

Abstract Background Invasive micropapillary carcinoma (IMPC) is an unusual and distinct subtype of invasive breast tumor with high propensity for regional lymph node metastases. This study was to identify risk factors accounting for IMPC of the breast and to develop a nomogram to preoperatively predict the probability of lymph node involvement. Methods A retrospective review of the clinical and pathology records was performed in patients diagnosed with IMPC between 2003 and 2014 from Surveillance, Epidemiology, and End Results (SEER) database. The cohort was divided into training and validation sets. Training set comprised patients diagnosed between 2003 and 2009, while validation set included patients diagnosed thereafter. A logistic regression model was used to construct the nomogram in the training set and then varified in the validation set. Nomogram performance was quantified with respect to discrimination and calibration using R 3.4.1 software. Results Overall, 1407 patients diagnosed with IMPC were enrolled, of which 527 in training set and 880 in validation set. Logistic regression analysis indicated larger lesions, younger age at diagnosis, black ethnic and lack of hormone receptor expression were significantly related to regional nodes involvement. The AUC of the nomogram was 0.735 (95% confidential interval (CI) 0.692 to 0.777), demonstrating a good prediction performance. Calibration curve for the nomogram was plotted and the slope was close to 1, which demonstrated excellent calibration of the nomogram. The performance of the nomogram was further validated in the validation set, with AUC of 0.748 (95% CI 0.701 to 0.767). Conclusions The striking difference between IMPC and IDC remains the increased lymph node involvement in IMPC and therefore merits aggressive treatment. The nomogram based on the clinicalpathologic parameters was established, which could accurately preoperatively predict regional lymph node status. This nomogram would facilitate evaluating lymph node state preoperatively and thus treatment decision-making of individual patients.

Abstract Glutathione S‐transferase M (GSTM) family is concerned with oxidative stress, which is associated with breast carcinogenesis and chemotherapy response. The null polymorphism of GSTM1 gene results in a thorough absence of the enzyme function. Our study was to evaluate the association between GSTM1 null/present polymorphism and chemotherapy treatment outcome in breast cancer patients. A total of unrelated 714 patients with a histologically confirmed breast cancer were randomly selected from two independent cancer centers. Polymerase chain reaction was performed to analyze null/present genotypes of GSTM1 in our study. Our study found that the present genotype of GSTM1 was associated with a better relapse‐free survival (RFS) (P = .03) with adjusted hazard ratio (HR) [95% confidence interval (CI)] of 0.63 (95% CI: 0.42‐0.93). The present genotype of GSTM1 was significantly correlated with a better RFS compared with the null genotype in the nonchemotherapy group (HR = 0.17, 95% CI: 0.06‐0.50; P = 0.001), but no effect was observed in the chemotherapy group (HR = 0.81, 95% CI: 0.52‐1.26; P = 0.35). Moreover, the interaction between the GSTM1‐null/present genotype and adjuvant chemotherapy was significant (P = 0.04) in further analysis. Our study suggests that the GSTM1 polymorphism plays a complex role in influencing the chemotherapy response and breast cancer survival. It is suggested that the GSTM1‐present genotype might prevent progression in breast cancer patients. In the meanwhile, it could damage the benefit of adjuvant chemotherapy as well in certain ways.

Abstract Background This study aimed to investigate the clinical utility of serum and histological MMP-9 detection during neoadjuvant chemotherapy (NAC) for triple-negative breast cancer (TNBC). Methods A total of 303 TNBC patients who underwent weekly paclitaxel plus carboplatin treatments followed by surgical resection were included in this study. Enzyme-linked immunosorbent assay (ELISA) was used to detect the serum level of Matrix metalloproteinase-9 (sMMP-9) at baseline and prior to surgery. Immunohistochemistry was used to detect histological MMP-9 (hMMP-9) expression in patients with residual tumors after NAC. The value of MMP-9 to predict the response to NAC and patient survival was studied. Results Of the 303 patients, 103 (34.0%) patients experienced pathological complete response (pCR) after completion of NAC. Univariate and multivariate analyses revealed that the relative change in sMMP-9, rather than sMMP-9 at baseline or surgery, had a remarkable predictive value for pCR. Each 1 ng/ml decrease in sMMP-9 after NAC was shown to result in a 0.3% increase in pCR rate. Additionally, in survival analyses, hMMP-9 expression in residual tumors was independently correlated with disease-free survival for non-pCR responders (P

Toll-like receptor 3 (TLR3) is a viral sensor that induces apoptosis in response to double-stranded RNA (dsRNA). Common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development. However, all of the polymorphisms in the previous study were only markers of the TLR3 gene, not causative polymorphisms. In this study, we performed a case-control study focusing on the relationship between rs5743305 (−926T>A), a single nucleotide polymorphism (SNP) in the promoter region of TLR3, and breast cancer. We found that the genetic variant rs5743305 increased the risk of breast cancer under the dominant and codominant models (dominant model: AT+AA vs TT.: OR = 1.3023, 95%CI: 1.0778–1.5736, P = .0062; codominant model: AA vs. TT: OR = 1.3919, 95%CI: 1.0177–1.9036, P = .0384; AT vs. TT: OR = 1.2799, 95%CI: 1.0475–1.5639, P = .0158) but not under the recessive model (TT vs. AT+AA, OR = 1.2387, 95%CI: 0.9197–1.6682, P = .1588). The same trends were found in the age-adjusted logistic regression study and stage 2 study. Furthermore, the electrophoretic mobility shift assay (EMSA) and luciferase reporter assay showed that rs5743305 decreased the transcriptional activity of TLR3. There was consistently reduced TLR3 mRNA and protein expression in human breast cancer samples from patients with TLR3 − 926A. Therefore, TLR3 rs5743305 increases the risk of breast cancer by decreasing the transcriptional activity of TLR3. This study may provide a better understanding of the genetic architecture underlying disease susceptibility and may advance the potential for preclinical prediction in future genetic testing.

Abstract The aim of this study was to explore the independent prognostic factors related to postoperative recurrence‐free survival (RFS) in patients with breast phyllodes tumors (PTBs). A retrospective analysis was conducted in Fudan University Shanghai Cancer Center. According to histological type, patients with benign PTBs were classified as a low‐risk group, while borderline and malignant PTBs were classified as a high‐risk group. The Cox regression model was adopted to identify factors affecting postoperative RFS in the two groups, and a nomogram was generated to predict recurrence‐free survival at 1, 3, and 5 years. Among the 404 patients, 168 (41.6%) patients had benign PTB, 184 (45.5%) had borderline PTB, and 52 (12.9%) had malignant PTB. Fifty‐five patients experienced postoperative local recurrence, including six benign cases, 26 borderline cases, and 22 malignant cases; the three histological types of PTB had local recurrence rates of 3.6%, 14.1%, and 42.3%, respectively. Stromal cell atypia was an independent prognostic factor for RFS in the low‐risk group, while the surgical approach and tumor border were independent prognostic factors for RFS in the high‐risk group, and patients receiving simple excision with an infiltrative tumor border had a higher recurrence rate. A nomogram developed based on clinicopathologic features and surgical approaches could predict recurrence‐free survival at 1, 3, and 5 years. For high‐risk patients, this predictive nomogram based on tumor border, tumor residue, mitotic activity, degree of stromal cell hyperplasia, and atypia can be applied for patient counseling and clinical management. The efficacy of adjuvant radiotherapy remains uncertain.

The PI3K pathway is altered across various cancer types. Here the authors use amplicon exon sequencing to analyze the landscape of somatic mutations affecting the PI3K pathway specifically in breast cancer patients in China.

Abstract Background Emerging evidence suggests molecular and phenotypic association between treatment resistance and epithelial–mesenchymal transition (EMT) in cancer. Compared with the well-defined molecular events of miR-200a in EMT, the role of miR-200a in therapy resistance remains to be elucidated. Methods Breast cancer cells transfected with mimic or inhibitor for miR-200a was assayed for chemoresistance in vitro. miR-200a expression was assessed by quantitative real-time PCR (qRT-PCR) in breast cancer patients treated with preoperative chemotherapy. Luciferase assays, cell proliferation assay were performed to identify the targets of miR-200a and the mechanism by which it promotes treatment resistance. Survival analysis was used to evaluate the prognosis value of miR-200a. Results In this study, our results showed ectopic expression of miR-200a promotes chemoresistance in breast cancer cell lines to several chemotherapeutic agents, whereas inhibition of miR-200a enhances gemcitabine chemosensitivity in resistance cancer cells. We found overexpression of miR-200a was closely associated with poor response to preoperative chemotherapy and poor prognosis in breast cancer patients. Furthermore, knockdown of YAP1 and TP53INP1 phenocopied the effects of miR-200a overexpression, and confirmed that TP53INP1 is a novel target of miR-200a. Remarkably, TP53INP1 expression is inversely correlated with miR-200a expression in Breast cancer cell lines. Taken together, these clinical and experimental results demonstrate that miR-200a is a determinant of chemoresistance of breast cancer. Conclusions Upregulated miR-200a enhances treatment resistance via antagonizing TP53INP1 and YAP1 in breast cancer.

Toll-like receptor 3 (TLR3) is a receptor recognizing double-stranded RNA (dsRNA) from viruses as well as from lytic mammalian cells. In the present study, we performed a two-stage association study (n = 3,551) and found that the minor alleles of two SNPs (the T-allele of rs5743312 and the T-allele of rs3775296) conferred increased risks of breast cancer incidence. The adjusted odds ratios (ORs) were 2.281 (P = 7.01 × 10−5) and 2.086 (P = 8.69 × 10−5), respectively. Specifically, the susceptibility variants within TLR3 were significantly associated with larger tumor size (adjusted P-values: 0.004 for rs5743312 and 0.004 for rs3775296). Furthermore, we investigated the biological function of the TLR3 protein in breast cancer cell lines. Notably, the stable expression of TLR3 directly inhibited cell proliferation both in vitro and in vivo. We also verified that TLR3 conferred less invasive phenotypes on breast cancer cells by regulating the mRNA expression of a panel of genes. TLR3-mediated inhibition of proliferation was caused by downregulation of the EGFR/PI3K/AKT pathway. In summary, our findings strongly suggest that common genetic changes in the TLR3 gene may influence breast cancer susceptibility and development, and TLR3 plays a negative regulatory role in the initiation and progression of human breast cancer cells, at least in part by downregulating the EGFR/PI3K/AKT pathway.

Chemotherapeutic resistance in triple-negative breast cancer (TNBC) has brought great challenges to the improvement of patient survival. The mechanisms of taxane chemoresistance in TNBC have not been well investigated. Our results illustrated C-C motif chemokine ligand 20 (CCL20) was significantly elevated during taxane-containing chemotherapy in breast cancer patients with nonpathologic complete response. Furthermore, CCL20 promoted the self-renewal and maintenance of breast cancer stem cells (BCSCs) or breast cancer stem-like cells through protein kinase Cζ (PKCζ) or p38 mitogen-activated protein kinase (MAPK)-mediated activation of p65 nuclear factor kappa B (NF-κB) pathway, significantly increasing the frequency and taxane resistance of BCSCs. Moreover, CCL20-promoted NF-κB activation increased ATP-binding cassette subfamily B member 1 (ABCB1)/multidrug resistance 1 (MDR1) expression, leading to the extracellular efflux of taxane. These results suggested that chemotherapy-induced CCL20 mediated chemoresistance via up-regulating ABCB1. In addition, NF-κB activation increased CCL20 expression, forming a positive feedback loop between NF-κB and CCL20 pathways, which provides sustained impetus for chemoresistance in breast cancer cells. Our results suggest that CCL20 can be a novel predictive marker for taxane response, and the blockade of CCL20 or its downstream pathway might reverse the taxane resistance in breast cancer patients.

Epithelial-to-mesenchymal transition (EMT) facilitates tumor metastasis. Twist is a basic helix-loop-helix protein that modulates many target genes through E-box-responsive elements. There are two twist-like proteins, Twist-1 and Twist-2, sharing high structural homology in mammals. Twist-1 was found to be a key factor in the promotion of metastasis of cancer cells, and is known to induce EMT. Twist-1 participation in carcinoma progression and metastasis has been reported in a variety of tumors. However, controversy exists concerning the correlation between Twist-1 and prognostic value with respect to carcinoma. A systematic review and meta-analysis were performed to determine whether the expression of Twist-1 was associated with the prognosis of carcinoma patients. This analysis included 17 studies: four studies evaluated lung cancer, three evaluated head and neck cancer, two evaluated breast cancer, two evaluated esophageal cancer, two evaluated liver cancer and one each evaluated osteosarcoma, bladder, cervical and ovarian cancer. A total of 2006 patients were enrolled in these studies, and the median trial sample size was 118 patients. Twist-1 expression was associated with worse overall survival (OS) at both 3 years (hazard ratio “HR” for death = 2.13, 95% CI = 1.86 to 2.45, p < 0.001) and 5 years (HR for death = 2.01, 95% CI = 1.76 to 2.29, p < 0.001). Expression of Twist-1 is associated with worse survival in carcinoma.

After the publication of this work [1] an error in Fig. 1c was brought to our attention: the Western blots for PRDX6 and β-actin were similar to those shown in lanes 5-6 of Fig. 4g. To verify these findings, we have repeated this experiment and the results are shown in a new Fig. 1c below. The repeated experimental results are consistent with the previously reported findings in the original study [1] and the functional role for PRDX6 in malignant progression of human cancer including breast cancer has been widely documented and recognized in numerous other studies [2]. We apologize for the error. However, this correction does not affect the conclusions of the article.

Toll-like receptors (TLRs) regulate the balance between the innate and adaptive immune responses. Missense single nucleotide polymorphisms (SNPs) in TLRs might be functional and thus influence the risks of chronic infection and cancer development. Here, we investigated the association of two missense SNPs, rs3775291 (c.1234G>A) in the TLR3 gene and rs4833095 (c.743T>C) in the TLR1 gene, with relapse-free survival (RFS) in a cohort of prospectively observed breast cancer patients.In this prospective observational study, rs3775291 in TLR3 and rs4833095 in TLR1 were genotyped in 715 patients with primary breast cancer in a Chinese population.Univariate analysis revealed that the patients with the AA genotype of rs3775291 had a shorter RFS compared with those carrying the G allele in the recessive model (P

Nucleolar spindle-associated protein (NuSAP1) is an important mitosis-related protein, and aberrant NuSAP1 expression is associated with abnormal spindles and mitosis. This study investigated the prognostic value of NuSAP1 in breast cancer.Two sets of tissue microarrays (TMAs) that included samples from 450 breast cancer patients were constructed, of which 250 patients were training set and the other 200 patients were validation set. Immunohistochemical staining was performed to determine the NuSAP1 levels. A Kaplan-Meier analysis was used to estimate the prognostic value of NuSAP1 in breast cancer. A stepwise Cox analysis was performed to construct a risk-prediction model for triple-negative breast cancer (TNBC). All statistical analysis was performed with SPSS software.There were 108 (43.5%) and 88 (44.0%) patients expressed NuSAP1 in the training set and validation set respectively. High levels of NuSAP1 expression were related to poor disease-free survival (DFS) in both training (P = 0.028) and validation (P = 0.006) cohorts, particularly in TNBC. With combination of two cohorts, both NuSAP1 (HR = 4.136, 95% CI: 1.956-8.747, P < 0.001) and BRCA1 (HR = 0.383, 95% CI: 0.160-0.915, P = 0.031) were independent prognostic indicators of DFS in TNBC. A receiver operating characteristic (ROC) analysis revealed that the combination of NuSAP1 and BRCA1 significantly improved the prognostic power compared with the traditional model (0.778 versus 0.612, P < 0.001).Our study confirms the prognostic value of NuSAP1 in breast cancer. The combination of NuSAP1 and BRCA1 could improve the DFS prediction accuracy in TNBC.

The purpose of this study was to determine the prognostic role of ten eleven translocation (TET) family proteins and DNA glycosylase (TDG) in patients with early breast cancer (EBC).Expression of mRNAs encoding TET1-3 and TDG in 162 breast cancer tissues was quantified using real-time polymerase chain reaction analysis. The general characteristics of patients and clinicopathologic factors were collected. Estimation of patient survival was calculated using the Kaplan-Meier method, and independent prognostic indicators were analyzed using Cox regression analysis.The level of TET1 mRNA was significantly related to overall survival (OS) (P = 0.022). Multivariate analysis shows that the TNM stage was an independent predictor of disease-free survival (DFS) (HR = 1.761, 95% CI: 1.124-2.761, P = 0.014) and OS (HR = 2.135, 95% CI: 1.070-4.263, P = 0.032). Further, in patients with EBC who were treated with anthracyclines, Kaplan-Meier analysis indicates that the levels of TET3 and TDG mRNAs were related to DFS (P = 0.026 and 0.030, respectively), and multivariate analysis reveals that high levels of TET3 (HR = 1.944, 95% CI: 1.029-3.672, P = 0.040) and TDG (HR = 2.178, 95% CI: 1.140-4.163, P = 0.018) mRNAs were independent indicators of favorable DFS.Our study indicates that EBC patients with decreased expression of TET1 mRNA had worse OS and that the levels of TET3 and TDG mRNAs were independent prognostic factors for patients who received anthracycline chemotherapy.

To study the value of adjuvant tamoxifen (TAM) in premenopausal women with oestrogen receptor (ER)-positive breast cancer who received adjuvant cyclophosphamide, methotrexate and 5-fluorouracil (CMF) polychemotherapy. Methods: Four hundred and two premenopausal ER-positive breast cancer patients who received CMF chemotherapy between January 1990 and December 1999 were retrospectively studied. Disease-free survival (DFS) and overall survival (OS) were used to evaluate the clinical value of TAM therapy. The relationships between nodal status and TAM were also analysed. Results: After a mean of 41 months of follow-up, 43 (13.7%) patients died of breast cancer and 68 (19.9%) patients suffered recurrence. There was a significant difference between TAM and non-TAM treatment groups for DFS (p = 0.0058), but no significant difference for OS. For node-negative patients, there was no significant difference between the TAM and non-TAM treatment groups for either DFS or OS. For node-positive patients, the difference between TAM and non-TAM treatment groups was significant for both DFS and OS (p = 0.0497 and p = 0.0285, respectively). Conclusion: TAM resulted in additional benefit to premenopausal patients with node-positive ER-positive breast cancer who received the CMF polychemotherapy regimen.

PURPOSE: Neoadjuvant chemotherapy (NCT) is a standard treatment option for locally advanced breast cancer. However, the lack of an efficient method to predict treatment response and patient prognosis hampers the clinical evaluation of patient eligibility for NCT. An elevated lymphocyte-to-monocyte ratio (LMR) has been reported to be associated with a favorable prognosis for certain hematologic malignancies and for nasopharyngeal carcinoma; however, this association has not been investigated in breast cancer. The purpose of this study was to evaluate whether pre-NCT LMR analysis could predict the prognosis of patients with locally advanced breast cancer. METHODS: A retrospective cohort of 542 locally advanced breast cancer patients (T3/T4 and/or N2/N3 disease) receiving NCT followed by radical surgery was recruited between May 2002 and August 2011 at the Fudan University Shanghai Cancer Center. Counts for pre-NCT peripheral absolute lymphocytes and monocytes were obtained and used to calculate the LMR. RESULTS: Univariate and multivariate analysis revealed that higher LMR levels (≥4.25) were significantly associated with favorable DFS (P = 0.009 and P = 0.011, respectively). Additionally, univariate analysis revealed that a higher lymphocyte count (≥1.5×109/L) showed borderline significance for improved DFS (P = 0.054), while a lower monocyte count (

The study was to estimate the likelihood of axillary downstaging and to identify the factors predicting a pathologically node negative status after neoadjuvant chemotherapy (NAC) with or without trastuzumab in HER2-positive breast cancer.Patients with HER2-positive, stage IIa-IIIc breast cancer were enrolled. Axillary status was evaluated by palpation and fine needle aspiration (FNA) before NAC. All patients received 4-6 cycles of PCrb (paclitaxel 80 mg/m2 and carboplatin AUC = 2 d1, 8, and 15 of a 28-day cycle, or paclitaxel 175 mg/m2 and carboplatin AUC = 6 every-3-week) and were non-randomly administered trastuzumab (2 mg/kg weekly or 6 mg/kg every-3-week) or not. After NAC, each patient underwent standard axillary lymph node dissection and breast-conserving surgery or mastectomy. And some patients received sentinel lymph node biopsy (SLNB) before axillary dissection.Between November-2007 and June-2013, 255 patients were enrolled. Of them, 157 were confirmed as axillary node positive by FNA (group-A) and 98 as axillary node negative either by FNA or impalpable (group-B). After axillary dissection, the overall pathologically node negative rates (pNNR) were 52.9% in group-A and 69.4% in group-B. The ER-poor/HER2-positive subtype acquired the highest pNNR (79.6% in group-A and 87.9% in group-B, respectively) and the lowest rate of residual with ≥4 nodes involvement (1.9% and 3%, respectively) after PCrb plus trastuzumab. In multivariate analysis, trastuzumab added and ER-poor status were independent factors in predicting a higher pNNR in HER2-positive breast cancer. Forty-six tested patients showed that the ER-poor/HER2-positive subtype acquired a considerable high pNNR and axillary status with SLNB was well macthed with the axillary dissection.ER-poor/HER2-positive subtype of breast cancer is a potential candidate for undergoing sentinel lymph node biopsy instead of regional node dissection for accurate axillary evaluation after effective downstaging by neoadjuvant chemo-trastuzumab therapy.

Breast cancer remains a major cause of death in women worldwide, and tumor metastasis is the leading cause of death in breast cancer patients after conventional treatment. Chronic inflammation is often related to the occurrence and growth of various malignancies. This study evaluated the prognosis of breast cancer patients based on contributors to the innate immune response: myeloid differentiation primary response 88 (MyD88) and Toll-like receptor 4 (TLR4).We analyzed data from 205 breast invasive ductal carcinoma (IDC) patients who were treated at the Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, from 2002 to 2006. Overall survival (OS) and disease-free survival (DFS) were compared.In total, 152 patients (74.15%) were disease-free without relapse or metastasis, whereas 53 (25.85%) patients developed recurrence or metastasis. A significant positive correlation was observed between MyD88 and TLR4 expression (p

BACKGROUND: Tumor size is one of the most important factors in making clinical and pathological assessment of breast cancer. In the present study, we aimed to determine whether the preoperative measurement of tumor size, by imaging modalities, deviate from the postoperative pathological measurement in breast cancer. PATIENTS AND METHODS: 1296 patients diagnosed with invasive ductal breast carcinoma (IDC) during 2007 and 2009 were involved. Pre- and postoperative measurements of tumor size were compared using paired t-test and Chi-square test. RESULTS: The mean maximum diameters of tumors by imaging modalities and pathology were 27.9 mm and 22.4 mm, respectively. There was a statistically significant difference of 5.5 mm (95% CI: 4.7-6.2, p

Invasive micropapillary carcinoma (IMPC) of the breast is a rare subtype of breast cancer that is associated with a high incidence of regional lymph node metastases and a poor clinical outcome. However, the clinico-pathological features and prognostic factors of IMPC are not well understood.A total of 188 IMPC cases and 1,289 invasive ductal carcinoma (IDC) cases were included. The clinical features, breast cancer-specific survival (BCSS) and recurrence/metastasis-free survival (RFS) of the patients were compared between these two groups.The IMPC patients exhibited more features of aggressive carcinoma than the IDC patients, including larger tumor size, higher tumor stage, a greater proportion of nodal involvement and an increased incidence of lymphovascular invasion. Patients with IMPC had lower 5-year BCSS and RFS rates (75.9% and 67.1%, respectively) than patients with IDC (89.5% and 84.5%, respectively). Compared to IDC patients, the patients with IMPC had a significantly higher percentage of stage III breast cancer (51.3% versus 21.7%). In a stage-matched Kaplan-Meier analysis, the patients with stage III IMPC had lower 5-year BCSS and RFS rates than patients with stage III IDC (BCSS, P = 0.004; RFS, P = 0.034). A multivariate analysis revealed that TNM stage was an independent prognostic factor for patients with IMPC. The proportion of cancers with a luminal-like subtype was significantly higher in IMPC than in IDC (P

BACKGROUND: Reduced overall survival has been observed in patients with left-sided versus right-sided breast cancer due to cardiac toxicity after radiotherapy. However, the effect of laterality and primary tumor site on breast cancer-specific mortality (BCSM) remains unclear. PATIENTS AND METHODS: We analyzed data from 305,443 women ages 20- to 79-years-old diagnosed with breast cancer between 1990 and 2009. The data were obtained from the population-based Surveillance, Epidemiology, and End Results (SEER) program of the U.S. National Cancer Institute. The survival outcomes with regard to laterality and primary tumor site were compared using univariate and multivariate (Cox proportional hazards regression model) methods. RESULTS: In the multivariate analysis, BCSM was affected by the primary tumor site (P

BACKGROUND: Postmastectomy breast reconstruction is widely used in breast cancer patients for its aesthetic effect. Although several studies have casted suspicion upon the oncological safety of immediate breast reconstruction after mastectomy, the potential impact of different reconstruction methods on patient survival remains unclear. PATIENTS AND METHODS: We identified 35,126 female patients diagnosed with breast cancer from January 1, 1998 to December 31, 2002 in the Surveillance, Epidemiology, and End Results database. Breast cancer-specific survival (BCSS) and overall survival (OS) were compared among patients who underwent mastectomy with or without immediate breast reconstruction (autologous reconstruction or implant reconstruction) using Cox proportional hazard regression models. RESULTS: In multivariate analysis unadjusted for family income, patients undergoing immediate postmastectomy reconstruction exhibited improved BCSS [POOLED reconstruction (any types of reconstruction): hazard ratio (HR) = 0.87, 95% confidence interval (CI) 0.80-0.95, P = 0.001] and OS (pooled reconstruction: HR = 0.70, 95% CI 0.65-0.75, P

The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins.

BACKGROUND AND AIM: We investigated the prognostic importance of dickkopf-1(DKK1) and beta-catenin expression in triple negative breast cancers. METHODS: The expression of DKK1 and beta-catenin was evaluated in breast cell lines using RT-PCR and western blot. Immunohistochemistry was used to characterize the expression pattern of DKK1 and beta-catenin in 85 triple negative breast cancers and prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression modeling. RESULTS: The expression of DKK1 was confirmed in hormone-resistant breast cell lines MDA-MB-231, MDA-MB-231-HM and MDA-MB-435. Expression of DKK1 in triple negative breast cancers correlated with cytoplasmic/nuclear beta-catenin (p = 0.000). Elevated expression of DKK1 and cytoplasmic/nuclear beta-catenin in triple negative cancers indicate poor outcome of patients. DKK1 was also a prognostic factor for patients with earlier stage or no lymph node metastasis. CONCLUSION: DKK1 together with beta-catenin might be important prognostic factors in triple negative breast carcinoma. DKK1 might be a valuable biomarker in predicting the prognosis of patients with earlier stage or no lymph node metastasis. It is possible that through further understanding of the role of Wnt/beta-catenin pathway activation, beta-catenin would be a potential therapeutic target for the triple negative breast cancer.

BACKGROUND: A few polymorphisms are located in the mature microRNA sequences. Such polymorphisms could directly affect the binding of microRNA to hundreds of target mRNAs. It remains unknown whether rs4919510:C>G located in the mature miR-608 alters breast cancer susceptibility. METHODS: The association of rs4919510:C>G with risk and pathologic features of breast cancer were investigated in two independent case-control studies, the first set including 1,138 sporadic breast cancer patients (including 927 invasive ductal carcinoma patients, 777 of them with known subtypes: 496 luminal-like, 133 HER2-positive, and 148 triple-negative) and 1,434 community-based controls, and the second set including 294 familial/early-onset breast cancer patients and 500 hospital-based cancer-free controls. Odds ratios (ORs) were estimated by logistic regression. Predicted targets of miR-608 and complementary sequences containing rs4919510:C>G were surveyed to reveal potential pathological mechanism. RESULTS: In the first set, although rs4919510:C>G was unrelated to breast cancer in general patients, variant genotypes (CG/GG) were specifically associated with increased risk of HER2-positive subtype (Adjusted OR = 1.97, 95% CI, 1.34-2.90 in the recessive model). Variant G-allele was the risk allele with OR of 1.62 (95% CI, 1.23-2.15). Patients carrying GG-genotype also had larger HER2-positive tumors (P for Kruskal-Wallis test = 0.006). The relationship between rs4919510:C>G and risk of HER2-positive subgroup was validated in the second set (Bonferroni corrected P = 0.06). The adjusted combined OR (total 164 HER2-positive cases) in the recessive model was 1.97 (95% CI, 1.43-2.72) for GG genotype (corrected P = 1.1 × 10(-4)). Bioinformatic analysis indicated that, HSF1, which is required for HER2-induced tumorigenesis, might be a target of miR-608. The minimum free-energy of ancestral-miR-608 (C-allele) binding to HSF1 is -35.9 kcal/mol, while that of variant-form (G-allele) is -31.5 kcal/mol, indicating a lower affinity of variant-miR-608 to HSF1 mRNA. CONCLUSION: rs4919510:C>G in mature miR-608 may influence HER2-positive breast cancer risk and tumor proliferation.

BACKGROUND: To evaluate the relationship between body mass index (BMI) and response to neoadjuvant chemotherapy (NCT) for breast cancer among Chinese women. PATIENTS AND METHODS: A total of 307 eligible patients were assigned to receive four cycles of paclitaxel and carboplatin before standard surgery for breast cancer from 2007 to 2011 at Shanghai Cancer Hospital. The patients were categorized as obese, overweight, normal weight, or underweight based on BMI according to World Health Organization (WHO) criteria. Pathological complete response (pCR) was defined as no invasive cancer in the breast or axillary tissue. A logistic regression and the Chi-squared test were used for detecting the predictors of pCR and determining the relationship between BMI category and pCR rate in the subgroup analysis with respect to other variables. RESULTS: Categorical BMI, estrogen receptor (ER), and progesterone receptor (PR) status were independent predictors of pCR according to the multivariate analysis. Patients with BMI≥25 were less likely to achieve a pCR to NCT compared with patients with BMI

Previous studies have shown that let-7 can repress the post-transcriptional translation of LIN28, and LIN28 in turn could block the maturation of let-7, forming a double-negative feedback loop. In this study, we investigated the effect of germline genetic variants on regulation of the homeostasis of the let-7/LIN28 loop and breast cancer risk. We initially demonstrated that the T/C variants of rs3811463, a single nucleotide polymorphism (SNP) located near the let-7 binding site in LIN28, could lead to differential regulation of LIN28 by let-7. Specifically, the C allele of rs3811463 weakened let-7-induced repression of LIN28 mRNA, resulting in increased production of LIN28 protein, which could in turn down-regulate the level of mature let-7. This effect was then validated at the tissue level in that the normal breast tissue of individuals with the rs3811463-TC genotype expressed significantly lower levels of let-7 and higher levels of LIN28 protein than those individuals with the rs3811463-TT genotype. Because previous in vitro and ex vivo experiments have consistently suggested that LIN28 could promote cellular transformation, we then systematically evaluated the relationship between rs3811463 as well as other common LIN28 SNPs and the risk of breast cancer in a stepwise manner. The first hospital-based association study (n = 2,300) demonstrated that two SNPs were significantly associated with breast cancer risk, one of which was rs3811463, while the other was rs6697410. The C allele of the rs3811463 SNP corresponded to an increased risk of breast cancer with an odds ratio (OR) of 1.25 (P = 0.0091), which was successfully replicated in a second independent study (n = 1,156) with community-based controls. The combined P-value of the two studies was 8.0 × 10⁻⁵. Taken together, our study demonstrates that host genetic variants could disturb the regulation of the let-7/LIN28 double-negative feedback loop and alter breast cancer risk.

PURPOSE: To investigate the relationship between age and axillary lymph node (LN) involvement in Chinese breast cancer patients, and to replicate a recently identified piecewise relationship between age and LN involvement. METHODS: A dataset, consisting of 3,715 patients (with complete information on study variables) with operable breast cancer consecutively surgically treated between 1996 and 2006, was derived from the database of Shanghai Cancer Hospital. Univariate and multivariate logistic regression were employed to analyze the relationship between age and LN. We subsequently performed a similar analysis on another dataset including 1,832 consecutive patients treated between 2007 and 2008 to replicate our findings in the first dataset. RESULTS: A U-shaped relationship (previously observed in two European populations) between age and LN status failed to be replicated in our dataset of Chinese patients. Instead, we observed a linear rather than piecewise relationship. After multivariate adjustment, the linear relationship was still present. Moreover, the interaction between age and LN involvement was not modified by tumor size. The odds of LN involvement decreased by 1.5% for each year increase in age (OR 0.985, 95% CI 0.979-0.991, P

PURPOSE: Previous studies have suggested that postmenopausal women with breast cancer who present with wild-type CYP2D6 may actually have similar or superior recurrence-free survival outcomes when given tamoxifen in place of aromatase inhibitors (AIs). The present study established a CYP2D6 multiple-genotype-based model to determine the optimal endocrine therapy for patients harboring wild-type CYP2D6. METHODS: We created a Markov model to determine whether tamoxifen or AIs maximized 5-year disease-free survival (DFS) for extensive metabolizer (EM) patients using annual hazard ratio (HR) data from the BIG 1-98 trial. We then replicated the model by evaluating 9-year event-free survival (EFS) using HR data from the ATAC trial. In addition, we employed two-way sensitivity analyses to explore the impact of HR of decreased-metabolizer (DM) and its frequency on survival by studying a range of estimates. RESULTS: The 5-year DFS of tamoxifen-treated EM patients was 83.3%, which is similar to that of genotypically unselected patients who received an AI (83.7%). In the validation study, we further demonstrated that the 9-year EFS of tamoxifen-treated EM patients was 81.4%, which is higher than that of genotypically unselected patients receiving tamoxifen (78.4%) and similar to that of patients receiving an AI (83.2%). Two-way sensitivity analyses demonstrated the robustness of the results. CONCLUSIONS: Our modeling analyses indicate that, among EM patients, the DFS/EFS outcome of patients receiving tamoxifen is similar to that of patients receiving an AI. Further prospective clinical trials are needed to evaluate the value of the CYP2D6 genotype in the selection of endocrine therapy.