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Background: Breast cancer (BRCA) represents a significant health challenge for women globally, with refractory cases showing resistance to current therapeutic strategies. The discovery of novel molecular markers and therapeutic targets is critical for improving outcomes in these patients. The primary aim of this study is to elucidate the role of tumor protein D52 (TPD52) as a novel molecular marker and potential therapeutic target to improve outcomes for BRCA patients., Methods: Using bioinformatics methods, we screened and evaluated the expression, prognosis, and associated mechanisms of TPD52 in BRCA. Two hundred and thirty-eight BRCA cases and 19 control cases were collected from Shanghai First Maternity and Infant Hospital, and the protein expression of TPD52 was detected by immunohistochemistry, and the correlation between TPD52 and the prognosis of BRCA was analyzed., Results: The expression of TPD52 in BRCA tissues was significantly higher than that in the control (P<0.001), displaying a strong association with key clinical variables, concurrently indicating an unfavorable prognostic implication. The survival analysis revealed high TPD52 expression was an independent adverse prognostic factor for overall (P=0.008) and disease-specific survival (P=0.005). Gene set enrichment analysis showed that TPD52 negatively correlated with estradiol, AMP-activated protein kinase, and other responses. Immune infiltration analysis showed that TPD52 was associated with immune cell infiltration, Th-1/Th-2 cell balance, and immune defense cells such as dendritic and plasmacytoid dendritic cells. It is further found that high TPD52 expression is associated with progression-free and disease-free survival from the analysis of immunohistochemical data of the patients at our hospital., Conclusions: In summary, TPD52 may serve as an independent prognostic biomarker for BRCA, which may represent a promising novel therapeutic target, particularly for the refractory estrogen receptor-positive (ER+)/progesterone receptor-positive (PR+)/human epidermal growth factor receptor 2-positive (HER2+) BRCA cases that have failed endocrine therapy and targeted treatment.

Purpose: How the neddylation pathway functions in breast tumor and regulation of estrogen receptor (ER) expression is rarely reported. The purpose of this study was to identify the role of neddylation in breast cancer and ER expression, and further explore the underlying mechanisms., Experimental Design: Expression patterns of nedd8-activating enzyme (NAE) and nedd8, two key proteins in the neddylation pathway, were examined in human breast specimens. ER-α expression was investigated using animal 18F-FES-PET/CT and immunoblotting upon NAE inhibitor MLN4924 treatment. Chromatin immunoprecipitation assay, luciferase reporter promoter assay, and the CRISPR-Cas9 system were used to elucidate the mechanism of ER-α regulation by MLN4924. The ER-positive breast cancer mouse model was used to determine the synergetic effect of MLN4924 and fulvestrant on tumor growth. All statistical tests were two-sided., Results: Both NAE1 and nedd8 expressions were higher in the ER-positive subgroup. Higher expressions of NAE1 and nedd8 indicated poorer prognosis. Importantly, ER-α expression was significantly downregulated upon MLN4924 treatment in vitro and in vivo . Mechanistically, MLN4924 treatment delayed serum and glucocorticoid-induced protein kinase (SGK) degradation and induced Forkhead box O3a (FOXO3a) nuclear export as well as decreased binding to the ESR1 promoter. Importantly, MLN4924 single or synergized with fulvestrant significantly suppressed the growth of ER-positive breast cancer in vitro and in vivo ., Conclusions: Our proof-of-principle study determines the activation of neddylation in breast tumor tissues for the first time and reveals a new ER-α regulatory mechanism, as well as further explores an effective approach to improve fulvestrant sensitivity through a neddylation inactivation combination., (©2019 American Association for Cancer Research.)

Objective: To investigate ovarian function and therapeutic efficacy among estrogen receptor (ER)-positive, premenopausal breast cancer patients treated with gonadotropin-releasing hormone agonist (GnRHa) and chemotherapy simultaneously or sequentially., Method: This study was a phase 3, open-label, parallel, randomized controlled trial (NCT01712893). Two hundred sixteen premenopausal patients (under 45 years) diagnosed with invasive ER-positive breast cancer were enrolled from July 2009 to May 2013 and randomized at a 1:1 ratio to receive (neo)adjuvant chemotherapy combined with sequential or simultaneous GnRHa treatment. All patients were advised to receive GnRHa for at least 2 years. The primary outcome was the incidence of early menopause, defined as amenorrhea lasting longer than 12 months after the last chemotherapy or GnRHa dose, with postmenopausal or unknown follicle-stimulating hormone and estradiol levels. The menstrual resumption period and survivals were the secondary endpoints., Result: The median follow-up time was 56.9 months (IQR 49.5-72.4 months). One hundred and eight patients were enrolled in each group. Among them, 92 and 78 patients had complete primary endpoint data in the sequential and simultaneous groups, respectively. The rates of early menopause were 22.8% (21/92) in the sequential group and 23.1% (18/78) in the simultaneous group [simultaneous vs. sequential: OR 1.01 (95% CI 0.50-2.08); p = 0.969; age-adjusted OR 1.13; (95% CI 0.54-2.37); p = 0.737]. The median menstruation resumption period was 12.0 (95% CI 9.3-14.7) months and 10.3 (95% CI 8.2-12.4) months for the sequential and simultaneous groups, respectively [HR 0.83 (95% CI 0.59-1.16); p = 0.274; age-adjusted HR 0.90 (95%CI 0.64-1.27); p = 0.567]. No significant differences were evident for disease-free survival (p = 0.290) or overall survival (p = 0.514) between the two groups., Conclusion: For ER-positive premenopausal patients, the sequential use of GnRHa and chemotherapy showed ovarian preservation and survival outcomes that were no worse than simultaneous use. The application of GnRHa can probably be delayed until menstruation resumption after chemotherapy.

Previous studies have reported that hypoxia-inducible factor (HIF)-1α confers endocrine resistance and that zoledronic acid (ZOL) decreases HIF‑1α expression in estrogen receptor‑positive breast cancer. The present study investigated the effect of the combination treatment with ZOL and fulvestrant and its possible mechanism for HIF‑1α inhibition in vitro and in vivo. First, cell proliferation, clonogenic ability and HIF‑1α expression by western blotting were determined in MCF‑7 breast cancer cells stably expressing HIF‑1α in vitro. Next, a mouse xenograft model was established with the HIF‑1α‑overexpressing MCF‑7 breast cancer cells, and treated with PBS, fulvestrant, ZOL or fulvestrant plus ZOL. Tumor volumes were compared and animal [18F]‑fluoromisonidazole (FMISO) positron emission tomography‑computer tomography (PET‑CT) was used to detect the hypoxic status of the xenograft tumors. Protein expression levels of HIF‑1α in the xenograft tumors were detected by immunohistochemistry and western blotting. The results demonstrated that the HIF-1α-overexpressing xenograft tumors grew faster and larger compared with control tumors. The animal [18F]‑FMISO PET‑CT also confirmed these results. [18F]‑FMISO uptake was significantly higher in HIF‑1α‑overexpressing xenograft tumors compared with control tumors. In addition, the combination treatment with ZOL and fulvestrant acted synergistically in the mouse xenograft model in vivo to significantly reduce tumor burden. Similarly, combination of ZOL and fulvestrant significantly reduced tumor cell growth in vitro. ZOL alone did not inhibit the tumor growth of MCF‑7 cells stably expressing HIF‑1α. Furthermore, ZOL significantly inhibited extracellular signal‑regulated kinase (ERK) 1/2 phosphorylation, while phosphoinositide 3‑kinase/AKT signaling was not affected. In conclusion, the present study demonstrated that ZOL significantly increased the sensitivity of breast cancer cells to fulvestrant through inhibition of the ERK/HIF-1α pathway.

Background: Studies have demonstrated that cysteine-rich 61 (CYR61) may be involved in tumor proliferation and invasion. However, the role of CYR61 plays in endocrine therapy response is largely unknown., Patients and Methods: We tested the levels of CYR61 expression of 36 primary breast cancer patients who received neo-adjuvant endocrine therapy for at least 3 months by immunohistochemistry staining before and after administrating letrozole, an oral non-steroidal aromatase inhibitor (AI) for the treatment of hormone-responsive breast cancer. The expression levels of CYR61 and ki67 were compared between pre-treatment and post-treatment samples by using the paired t test. Chi-square test was used to determine the relationship between baseline CYR61 expression and clinical response., Results: In the clinical case series analysis, a positive correlation was observed between baseline CYR61 expression and clinical outcomes (p=0.02). CYR61 expression was significantly increased in the residual tumors after treatment (indicating insensitivity to endocrine therapy) compared with that in the baseline biopsy samples, which was irrespective of the efficacy of primary endocrine treatment. In addition, the ki67 level was significantly decreased after neo-adjuvant endocrine therapy, compared with that in the baseline samples., Conclusion: This study provides evidence that CYR61 may confer the sensitivity to letrozole treatment and may offer an opportunity to target CYR61 to improve endocrine resistance in ER-positive breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

The prognosis for breast cancer occurs in young women is usually poor. The impact of different reproductive factors on disease characteristics is still largely unknown. We analyzed 261 patients aged ≤35 years old who were treated at the Cancer Hospital of Fudan University, Shanghai, China. The relationships between certain reproductive factors (age at menarche, parity, number of children, breastfeeding, history of abortion, age at first full-term pregnancy and oral contraceptive (OC) use) and disease characteristics were evaluated. Compared with patients who experienced fewer full-term pregnancies (<2 times), the patients with more full-term pregnancies (≥2 times) exhibited higher percentage of ER-positive tumors (61.5%) (P = 0.015), and patients whose age of menarche was ≥15 years exhibited a greater chance of PR-positive tumors (64.8%) (P = 0.036) compared with those whose age of menarche was <15 years old. Additionally, patients who had taken OCs were more likely to present with late-stage tumors (II stage or later) (87.5%) (P = 0.002) than patients who had never taken OCs. Our study provides evidence that women with more full-term pregnancies and later age at menarche are more possible to exhibit hormone receptor-positive tumors. Additionally, patients who have taken OCs are more likely to present with advanced disease.

Resistance is an obstacle to endocrine therapy for breast cancer. We measured levels of hypoxia-inducible factor (HIF)-1α in 52 primary breast cancer patients before and after receiving neoadjuvant endocrine therapy with letrozole for at least 3 months. Pre-treatment levels of HIF-1α were associated with negative clinical outcome. Furthermore, levels of HIF-1α were increased in post-treatment residual tumors compared with those in pre-treatment biopsy samples. In animal studies, xenografts stably expressing HIF-1α were resistant to endocrine therapy with fulvestrant compared with the effects in control xenografts. Additionally, HIF-1α transcription was inhibited by zoledronic acid, a conventional drug for the treatment of postmenopausal osteoporosis, and was accompanied by a marked inhibition of the RAS/MAPK/ERK1/2 pathway. HIF-1α is a determinant of resistance to endocrine therapy and should be considered as a potential therapeutic target for overcoming endocrine resistance in estrogen receptor (ER)-positive breast cancer. In addition, zoledronic acid may overcome endocrine resistance in ER-positive human breast cancer by targeting HIF-1α transcription through inhibition of the RAS/MAPK/ERK1/2 pathway. Clinical studies on the administration of zoledronic acid as a second line treatment in patients who failed endocrine therapy should be considered to improve therapeutic outcomes in breast cancer patients.

To evaluate whether chemotherapy is indispensable in elderly patients with early estrogen receptor (ER)-negative breast cancer and diabetes mellitus (DM), the data on 112 patients, ≥70 years of age, with early, operable ER-negative breast cancer who were treated at the Cancer Hospital of Fudan University, Shanghai, China, between 2000 and 2010, were analyzed. The overall survival (OS), disease-free survival (DFS), and breast cancer-specific survival (BCS) were compared. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of DM and chemotherapy for OS, DFS, and BCS. The univariate Cox regression analysis revealed that DM at diagnosis, the number of positive lymph nodes, and radiotherapy were associated with OS, the number of positive lymph nodes, human epidermal growth factor 2 (HER2/neu) status, and radiotherapy were associated with DFS, and the number of positive lymph nodes, tumor size, HER2/neu status, chemotherapy, and radiotherapy were associated with BCS. The subsequent multivariate analysis identified DM at diagnosis (hazard ratio [HR]=3.797; 95% confidence interval [CI], 1.515-9.520; P=0.004) as an independent prognostic factor for OS (with the addition of chemotherapy regimen). Chemotherapy was not an independent prognostic factor for either OS (HR=1.275; 95% CI, 0.614-2.646; P=0.515) or DFS (HR=0.849; 95% CI, 0.445-1.619; P=0.619) when other possible factors that may affect the results were adjusted. In conclusion, chemotherapy was not found to be indispensable for elderly (≥70 years of age) female patients with early ER-negative breast cancer with DM because, particularly in such patients, the treatment of DM may be more important compared with chemotherapy.