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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.

Aim: To correlate the relationship between the aggressiveness of breast cancer based on hormone receptor status with histopathological grading and staging of breast cancer. Methods. 193 patients of breast cancer were seen during a period of two years and 112 were included in the study. All the patients were subjected to appropriate surgery under general anesthesia and further treatment in the form of Chemotherapy/ Radiotherapy/ Hormonal therapy as indicated after obtaining the histopathological report. A biopsy was sent for detailed histopathological diagnosis including hormone receptor status. Observations were made and results were recorded. Patients were followed up as per the protocol. Results: Hormone receptor status was done in all the patients. 72 (64%) patients had ER/PR status positivity whereas 14 (13%) patients were ER/PR negative. All the cases were of infiltrating ductal carcinoma (IDC). Of these cases, 42 (37.5%) patients had IDC grade II and 70 (62.5%) patients had grade III. There was no grade I case in our study. Stage I cases comprised 2 (2%), Stage II 37 (33%), and Stage III 70 (62%) of patients. Whereas, 3 (3%) patients had stage IV disease or Metastatic breast cancer. Conclusion: Hormone receptors negative status in younger women in premenopausal status by itself is a poor prognostic factor. There is also a direct correlation between the hormone receptor (ER / PR) negativity and breast cancer aggressiveness with metastasis positive lymph node, larger tumor size, and higher histopathological gradation.

Breast cancers include a heterogeneous group of diseases with clinical behaviors that may vary according to the hormonal receptor status. However, limited knowledge is available on the role of breast cancer environmental and occupational risk factors in the onset of specific molecular disease phenotypes. Therefore, the aim of this review was to provide an overview on the possible correlation between occupational chemical exposures and breast cancers with a specific receptor pattern. Pubmed, Scopus, and ISI Web of Science databases were systematically reviewed to identify all the studies addressing chemical exposure in workplaces and risk of breast cancer classified according to the presence of estrogen and/or progesterone receptors. Some positive associations were reported between solvent, polycyclic aromatic hydrocarbon, organophosphoric insecticide, and synthetic fiber exposure and estrogen receptor-positive cases, while other investigations demonstrated a relationship with receptor-negative tumors or failed to detect any significant effect. Overall, further investigation should overcome limitations due to the self-reported information on work histories, the chemical classification in general categories, and the lack of environmental or biological monitoring exposure data. This may support the development of suitable and individually “tailored” occupational risk assessment and management strategies to protect the health of exposed workers, particularly those with hypersusceptibility conditions.

Introduction Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma). Materials and methods Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI. Results Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial–stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial–stromal ratio amongst all participants and among pre- and postmenopausal women separately. Conclusion Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer. Electronic supplementary material The online version of this article (10.1007/s10549-018-4768-0) contains supplementary material, which is available to authorized users.

// Yi-Zi Zheng 1, 2 , Lei Wang 1, 2 , Xin Hu 1 , Zhi-Ming Shao 1, 2, 3 1 Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Fudan University, Shanghai, China 2 Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China 3 Institutes of Biomedical Science, Fudan University, Shanghai, China Correspondence to: Xin Hu, e-mail: xinhu.nlorg@gmail.com Zhi-Ming Shao, e-mail: zhimingshao@yahoo.com Keywords: breast cancer, hormone receptor status, tumor size, breast cancer-specific mortality Received: March 06, 2015 Accepted: April 28, 2015 Published: May 11, 2015 ABSTRACT Background & Aims: The prognostic value of tumor size is variable. We aimed to characterize the interaction between tumor size and hormone receptor (HoR) status to determine breast cancer-specific mortality (BCSM). Methods: We used the Surveillance, Epidemiology and End Results (SEER) registry to identify 328, 870 female patients diagnosed with invasive breast cancer from 1990 through 2010. Primary study variables included tumor size, joint HoR status and their corresponding relationship. Kaplan-Meier and adjusted Cox proportional hazards models with interaction terms were utilized. Results: The multivariable analysis revealed a significant interaction between tumor size and HoR status ( P 50 mm had nearly identical BCSM rates ( P = 0.127, P = 0.099 and P = 0.370 for 51–60 mm, 71–80 mm and > 80 mm tumors, respectively), whereas BCSM was positively correlated with tumors 50 mm underscores the importance of individualized treatment. Our findings may contribute to a better understanding of breast cancer biology.

Introduction The aim of the study was to analyze clinicopathologic characteristics and survival and to identify prognostic factors for Chinese patients with HER2-positive metastatic breast cancer. Material and methods A total of 243 patients with HER2-positive metastatic breast cancer, treated during the period 2002 to 2009, were followed up from initial disease diagnosis to death or date of last follow-up (December 2011). Cumulative survival curves were created using Kaplan-Meier analysis with the log-rank test. Prognostic factors were analyzed by univariate and multivariate Cox proportional hazards regression analysis. Results During follow-up, 205 patients died, with a median OS of 27 months (95% CI: 23.5, 30.5 months), and the 1-, 3-, and 5-year survival rates were 84.4%, 38.6%, and 18.1%, respectively. The median OS of HR+ patients was significantly higher than that of HR– patients (p < 0.001). Surgery (hazard ratio = 0.60, p = 0.002), endocrine therapy (hazard ratio = 0.53, p < 0.01), and anti-HER2 therapy (hazard ratio = 0.63, p = 0.003) were favorable independent prognostic factors for patients with HER2-positive metastatic breast cancer. Conclusions These results indicated that surgical intervention, endocrine therapy, and anti-HER2 therapy were good for these HER2 positive patients with metastatic breast cancer, but ECOG performance status < 1 and metastasis to brain were unfavorable independent prognostic factors. HR status was not an independent prognostic factor.

Izhodišča. Enega izmed največjih izzivov pri zdravljenju raka dojk v zgodnjem stadiju predstavlja izbor bolnic s predvidenim agresivnejšim potekom bolezni, ki potrebujejo dopolnilno sistemsko zdravljenje. O tem se odločamo na podlagi različnih napovednih dejavnikov, kot so status pazdušnih bezgavk, velikost tumorja, stopnja diferenciacije, limfovaskularna invazija, starost bolnic, status hormonskih receptorjev, status HER2, v zadnjem času pa v ta namen ponekod uporabljajo tudi urokinazni aktivator plazminogena (uPA) in inhibitor aktivatorja plazminogena 1 (PAI-1). Vloga novejših napovednih dejavnikov v primerjavi s tradicionalnimi še ni povsem razjasnjena. Namen raziskave je bil ugotoviti vpliv posameznih dejavnikov na preživetje bolnic z rakom dojk brez zasevkov v bezgavkah, zdravljenih v Univerzitetnem kliničnem centru (UKC) Maribor. Hkrati sem želela tudi primerjati preživetje bolnic, zdravljenih v UKC Maribor, s slovenskim povprečjem. Bolnice in metode. Opravila sem retrospektivno analizo bolnic z invazivnim rakom dojk brez zasevkov v bezgavkah, ki so bile primarno zdravljene v UKC Maribor v letih 2000–2009. Podatke sem pridobila iz medicinske dokumentacije in jih dopolnila s podatki iz Registra raka Republike Slovenije, od koder sem pridobila tudi podatke o vseh primerljivih slovenskih bolnicah, zdravljenih v istem obdobju. Analizirala sem korelacije med napovednimi dejavniki in s pomočjo Coxove regresije in Coxovega modela sorazmernih tveganj opravila univariatne in multivariatne analize preživetja brez bolezni, celokupnega in specifičnega preživetja. Rezultati. Študijsko skupino je sestavljalo 858 bolnic s srednjim časom sledenja 101 mesec. Med bolnicami, zdravljenimi v UKC Maribor, in vsemi slovenskimi bolnicami ni bilo razlik v celokupnem (HR 1,07 95 % CI 0,91–1,27 p = 0,413) in specifičnem preživetju (HR 0,85 95 % CI 0,66–1,11 p = 0,234). Preživetje brez bolezni (HR 0,67 95 % CI 0,50–0,91 p = 0,010) in specifično preživetje (HR 0,53 95 % CI 0,30–0,94 p = 0,031) je bilo statistično značilno boljše v obdobju 2005–2009 v primerjavi z 2000–2004, pri celokupnem preživetju pa se je kazal enako usmerjen statistično neznačilen trend (HR 0,73 95 % CI 0,51–1,05 p = 0,087). Med napovednimi dejavniki so bile prisotne številne korelacije. V multivariatnih analizah so na preživetje brez bolezni najbolj vplivali starost ob diagnozi, vrednost uPA/PAI-1 in status estrogenskih receptorjev, na celokupno preživetje starost, stopnja diferenciacije in vrednost uPA/PAI-1, na specifično preživetje pa stopnja diferenciacije. Zaključki. Preživetje bolnic z rakom dojk brez zasevkov v bezgavkah, primarno zdravljenih v UKC Maribor v letih 2000–2009, je zelo visoko in enakovredno preživetju vseh primerljivih bolnic na ravni Slovenije. Kot najpomembnejša napovedna dejavnika sta se pri tej skupini bolnic izkazala vrednost uPA/PAI-1 in stopnja diferenciacije, ki sta klinično pomembno vplivala na preživetje brez bolezni, celokupno in specifično preživetje. Introduction. The choice of patients with an expected aggressive course of the disease who need adjuvant systemic treatment represents one of the main challenges of early stage breast cancer treatment. Prognostic factors, such as lymph node status, tumour size, grade, lymphovascular invasion, patient age, hormone receptor status, HER2 status, and more recently urokinase plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1), can be used to guide this decision. The significance of some novel prognostic factors in comparison with traditional factors is not yet completely understood. The purpose of this study was to determine the effect of different prognostic factors on survival in node-negative breast cancer patients treated in University Medical Centre Maribor. In addition, I wished to compare the survival of patients treated in Maribor with that of all Slovenian patients. Patients and methods. A retrospective analysis of lymph node-negative invasive breast cancer patients treated in University Medical Centre Maribor in the years 2000–2009 was performed. Data were obtained from patient medical records and from the Cancer Registry of Republic of Slovenia whence I also obtained information on all comparable Slovenian patients diagnosed in the same period. Correlations between different prognostic factors were analysed. Univariate and multivariate analyses of disease-free (DFS), overall (OS), and breast cancer specific survival (BCSS) were performed using the Cox regression and the Cox proportional hazards model. Results. The study group consisted of 858 patients with a median follow-up of 101 months. No differences were observed between the Maribor and Slovenian patients in terms of OS (HR 1.07 95% CI, 0.91–1.27 p=0.413) and BCSS (HR 0.85 95% CI, 0.66–1.11 p=0.234). DFS (HR 0.67 95% CI, 0.50–0.91 p=0.010) and BCSS (HR 0.53 95% CI, 0.30–0.94 p=0.031) were significantly better for patients diagnosed in the period 2005–2009 compared to 2000–2004 and a similar though unsignificant trend was observed for OS as well (HR 0.73 95% CI, 0.51–1.05 p=0.087). Many correlations existed between different prognostic factors. In multivariate analyses, DFS was particularly influenced by patient age at diagnosis, uPA/PAI-1 level and oestrogen receptor status, OS by age, grade and uPA/PAI-1 level, and BCSS by tumour grade. Conclusions. Survival of node-negative breast cancer patients treated in University Medical Centre Maribor in the period 2000–2009 was very good and not inferior to the survival of comparable patients at the national level. The most important prognostic factors in node-negative patients were uPA/PAI-1 level and tumour grade because they had a clinically important influence on DFS, OS and BCSS.

Survival analysis is a family of statistical procedures for data analysis for which the outcome variable of interest is time until an event occurs. The Cox model is the most widely used survival model in health sciences, but it is not the only model, parametric models in which the distribution of the event is specified in terms of unknown parameters. Over the last few years, there has been increased interest shown in the application of survival analysis based on Bayesian methodology. In this article, we consider Bayesian survival analysis to compare survival probability of hormone receptor status for breast cancer based on lognormal distribution estimated survival function. The Bayesian approach is implemented using WinBugs. © 2017 Inderscience Enterprises Ltd.

This is the peer reviewed version of the following article: Matejcic, M., De Batlle, J., Ricci, C., Biessy, C., Perrier, F., Huybrechts, I., ... Chajès, V. (2017). Biomarkers of folate and vitamin B12 and breast cancer risk: report from the EPIC cohort. International Journal of Cancer, 140(6), 1246-1259. https://doi.org/10.1002/ijc.30536, which has been published in final form at https://doi.org/10.1002/ijc.30536. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Epidemiological studies have reported inconsistent findings for the association between B vitamins and breast cancer (BC) risk. We investigated the relationship between biomarkers of folate and vitamin B12 and the risk of BC in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Plasma concentrations of folate and vitamin B12 were determined in 2,491 BC cases individually matched to 2,521 controls among women who provided baseline blood samples. Multivariable logistic regression models were used to estimate odds ratios by quartiles of either plasma B vitamin. Subgroup analyses by menopausal status, hormone receptor status of breast tumors (estrogen receptor [ER], progesterone receptor [PR] and human epidermal growth factor receptor 2 [HER2]), alcohol intake and MTHFR polymorphisms (677C > T and 1298A > C) were also performed. Plasma levels of folate and vitamin B12 were not significantly associated with the overall risk of BC or by hormone receptor status. A marginally positive association was found between vitamin B12 status and BC risk in women consuming above the median level of alcohol (ORQ4‐Q1 = 1.26; 95% CI 1.00–1.58; Ptrend = 0.05). Vitamin B12 status was also positively associated with BC risk in women with plasma folate levels below the median value (ORQ4‐Q1 = 1.29; 95% CI 1.02–1.62; Ptrend = 0.03). Overall, folate and vitamin B12 status was not clearly associated with BC risk in this prospective cohort study. However, potential interactions between vitamin B12 and alcohol or folate on the risk of BC deserve further investigation.

Journal article A recent two-stage genome-wide association study (GWAS) identified five novel breast cancer susceptibility loci on chromosomes 9, 10, and 11. To provide more reliable estimates of the relative risk associated with these loci and investigate possible heterogeneity by subtype of breast cancer, we genotyped the variants rs2380205, rs1011970, rs704010, rs614367, and rs10995190 in 39 studies from the Breast Cancer Association Consortium (BCAC), involving 49,608 cases and 48,772 controls of predominantly European ancestry. Four of the variants showed clear evidence of association (P â ¤ 3 Ã 10(-9) ) and weak evidence was observed for rs2380205 (P = 0.06). The strongest evidence was obtained for rs614367, located on 11q13 (per-allele odds ratio 1.21, P = 4 Ã 10(-39) ). The association for rs614367 was specific to estrogen receptor (ER)-positive disease and strongest for ER plus progesterone receptor (PR)-positive breast cancer, whereas the associations for the other three loci did not differ by tumor subtype. EC Seventh Framework Programme - grant number HEALTH-F2-2009-223175 peer-reviewed

Background Current evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups. Methods A total of 1633 BC cases and 1504 controls were enrolled in hospital-based case–control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status. Results Waist-to-hip ratio (WHR) of ≥0.95 was strongly associated with risk of BC compared to WHR ≤0.84 in both premenopausal (OR = 4.3; 95% CI: 2.9–6.3) and postmenopausal women (OR = 3.4; 95% CI: 2.4–4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI ≥30 were at lower risk compared to women with normal BMI (OR = 0.5; 95% CI: 0.4–0.8). A similar protective effect was observed in women who were postmenopausal for, Highlights • Waist-to-hip ratio increases risk of breast cancer (BC) irrespective of menopausal or hormone receptor status. • High body mass index (BMI) protects the risk of BC in premenopausal women. • The protection in risk of BC continues in women who have high BMI and are postmenopausal for

BACKGROUND: Less than 1% of all breast cancer cases are found in men, who reportedly have inferior outcomes compared with matched women patients. Ethnic differences may also affect their prognosis. Here, we investigated overall survival (OS) and major prognostic factors for male breast cancer (MBC) in a cohort of Egyptian patients. METHODS: We retrospectively analyzed OS in a cohort of 69 male patients with MBC who were surgically treated at the Mansoura Cancer Center, Egypt between 2000 and 2007. We registered demographic data, age, height, weight and body mass index, tumor size, histology, number of infiltrated axillary lymph nodes, hormone receptor (HR) status and metastatic presence, and TNM staging. Patients' OS was the primary endpoint. Patients received treatment to the medical standards at the time of their diagnosis. RESULTS: In the 69 patients who met the inclusion criteria and had complete stored patient data, tumors ranged from T1c to T3. We could gather cancer-related survival data from only 56 patients. The collective 5-year survival in this cohort was 46.4%. Only five patients had distant metastasis at diagnosis, but they showed a null percent 5-year survival, whereas those with no lymph node infiltration showed a 100% 5-year survival. Lymph node status and tumor grading were the only prognostic factors that significantly affected OS. CONCLUSIONS: Lymph node status and tumor grade are the most important prognostic factors for overall survival of MBC in Egyptian male patients; whereas even remarkably low HR expression in MBC did not significantly affect OS. Further research is needed to understand the factors that affect this disease.

Item does not contain fulltext Hormone receptor (HR) status is an important prognostic factor for patients with metastatic breast cancer (MBC) and is also correlated with other prognostic factors, such as initial lymph node status, HER2-Neu status and age. The prognostic value of these other factors, however, is unknown when stratified by HR positive versus HR negative patients. The aim of this study was to evaluate prognostic factors for MBC survival in relation to HR status. Dutch women diagnosed with breast cancer in 2003-2006 treated with curative intent who developed MBC within 5 years of follow-up were selected from the Netherlands cancer registry (N = 2,001). Independent prognostic factors for survival after metastatic occurrence were determined by multivariable Cox survival analyses stratified by HR status. Interactions between HR status and prognostic factors were determined. Median survival for MBC patients with HR negative (HR-) tumours was 8 months, compared to 19 months for HR positive (HR+) patients. The prognostic value of lymph node status, HER2-Neu status, adjuvant endocrine treatment and first-line palliative chemotherapy was dependent on HR status. Initial lymph node status was independently associated with survival in HR- patients, but not in HR+ patients. HER2-Neu positive status was associated with better survival in both HR+ and HR- patients, although the association was stronger in HR- patients. Similarly, patients treated with first-line palliative chemotherapy fared better, especially HR- patients. HR+ patients had worse survival if they had received adjuvant endocrine treatment. This study shows that the prognostic value of various factors depends on HR status in MBC. This information may help physicians to determine individual prognostic profiles and therapeutic strategies for MBC patients.

Human papilloma viruses (HPVs) are accepted as being carcinogenic in human cervical and anogenital cancers. The suspicion that HPVs may also have a role in human breast cancer is based on the identification of HPVs in human breast tumours and the immortalisation of normal human breast cells by HPV types 16 and 18. For this investigation, DNA that had been previously extracted and fresh frozen at −70°C from 50 unselected invasive ductal breast cancer specimens were screened by polymerase chain reaction (PCR) for HPV type 16, 18 and 33 gene sequences. We show that HPV 18 gene sequences are present in DNA extracted from breast tumours in Australian women. Overall, 24 (48%) of the 50 samples were HPV positive. Overall no correlations with tumour grade, patient survival, steroid receptor status, ERB-2, p53 expression and mutation were observed. Human papilloma viruses may have a role in human breast cancer. We speculate that HPVs may be transmitted by hand from the female perineum to the breast.

Molecular subtyping of breast cancer is necessary for therapy selection and mandatory for all breast cancer patients. Metabolic alterations are considered a hallmark of cancer and several metabolic drugs are currently being investigated in clinical trials. However, the dependence of metabolic alterations on breast cancer subtypes has not been investigated on -omics scale. Thus, 204 estrogen receptor positive (ER+) and 67 estrogen receptor negative (ER−) breast cancer tissues were investigated using GC–TOFMS based metabolomics. 19 metabolites were detected as altered in a predefined training set (2/3 of tumors) and could be validated in a predefined validation set (1/3 of tumors). The metabolite changes included increases in beta-alanine, 2-hydroyglutarate, glutamate, xanthine and decreases in glutamine in the ER− subtype. Beta-alanine demonstrated the strongest change between ER− and ER+ breast cancer (fold change = 2.4, p = 1.5E − 20). In a correlation analysis with genome-wide expression data in a subcohort of 154 tumors, we found a strong negative correlation (Spearman R = − 0.62) between beta-alanine and 4-aminobutyrate aminotransferase (ABAT). Immunohistological analysis confirmed down-regulation of the ABAT protein in ER− breast cancer. In a Kaplan–Meier analysis of a large external expression data set, the ABAT transcript was demonstrated to be a positive prognostic marker for breast cancer (HR = 0.6, p=3.2E-15).Biological significanceIt is well-known for more than a decade that breast cancer exhibits distinct gene expression patterns depending on the molecular subtype defined by estrogen receptor (ER) and HER2 status. Here, we show that breast cancer exhibits distinct metabolomics patterns depending on ER status. Our observation supports the current view of ER+ breast cancer and ER− breast as different diseases requiring different treatment strategies.Metabolic drugs for cancer including glutaminase inhibitors are currently under development and tested in clinical trials. We found glutamate enriched and glutamine reduced in ER− breast cancer compared to ER+ breast cancer and compared to normal breast tissues. Thus, metabolomics analysis highlights the ER− subtype as a preferential target for glutaminase inhibitors.For the first time, we report on a regulation of beta-alanine catabolism in cancer. In breast cancer, ABAT transcript expression was variable and correlated with ER status. Low ABAT transcript expression was associated with low ABAT protein expression and high beta-alanine concentration. In a large external microarray cohort, low ABAT expression shortened recurrence-free survival in breast cancer, ER+ breast cancer and ER− breast cancer.

Einleitung: Seit einigen Jahren werden epigenetische Aspekte in der Karzinogenese diskutiert und untersucht. Eine wesentliche Rolle spielen hierbei Histondeacetylasen (HDAC), die durch eine verstärkte Deacetylierung von DNA-Histonen aber auch anderer Zellzyklus-relevanter Proteine und Transkriptionsfaktoren zu vermehrter Zellproliferation und Angiogenese, Entdifferenzierung und Metastasierung führen. Basierend auf der Hypothese der modulierenden Wirkung von HDAC in der Karzinogenese entstanden neue Therapiekonzepte. In In-Vitro- und In-Vivo-Untersuchungen konnte gezeigt werden, dass eine HDAC-Inhibition zur Wachstumshemmung maligner Zellen führt. Im Jahr 2006 wurde der HDAC-Inhibitor Suberoylanilid-Hydroxamsäure (SAHA) für die Behandlung des kutanen T-Zell-Lymphoms zugelassen. Derzeit kommen mehrere HDAC-Inhibitoren in der Therapie verschiedener Tumorentitäten im Rahmen von klinischen Studien zum Einsatz. In der vorliegenden Arbeit wurde das Expressionsverhalten der Isoformen HDAC1, 2 und 3 im Mammakarzinom untersucht. Dabei wurden der prognostische Charakter sowie die Korrelationen der HDAC- Expression mit wichtigen klinisch-pathologischen Parametern im Mammakarzinom analysiert. Ziel war die Identifikation einer Subgruppe, die ein potentiell höheres Ansprechen auf HDACi haben könnte. Material und Methoden: Die Analyse erfolgte mittels eines Tissue-Microarrays (TMA) aus Formalin-fixiertem- Paraffin-eingebettetem (FFPE) Gewebe von insgesamt 238 Patientinnen mit invasivem Mammakarzinom, diagnostiziert am Institut für Pathologie der Universitätsmedizin Charité in den Jahren 1985-1999. An diesem erfolgten immunhistochemische Untersuchungen für HDAC1, 2 und 3. Die gefärbten Schnitte wurden im Anschluss digitalisiert und mittels virtueller Mikroskopie ausgewertet. Ergebnisse: HDAC1 zeigte eine starke Expression in 68 (32,7%), eine schwache Expression in 69 (33,2%) und eine fehlende Expression in 71 (34,1%) Fällen. Hinsichtlich der HDAC2-Expression stellte sich folgendes Expressionsprofil dar: starke Expression in 51 (24,1%), schwache Expression in 69 (32,5%) und fehlende Expression in 92 (43,4%) Fällen. HDAC3 wies eine starke Expression in 71 (31,7%), eine schwache Expression in 73 (32,6%) und eine fehlende Expression in 80 (35,7%) Proben auf. HDAC1 korrelierte signifikant mit einem positiven Hormonrezeptorstatus (p, Introduction: During the last years epigenetic aspects in carcinogenesis have been discussed and alterations caused by histonedeacetylases (HDAC) might play an important role. HDAC lead through increased deacetylation of DNA-histones and other proteins of cellcyclus to proliferation, angiogenesis, lower grading and metastasis in cancer cells. Based on this effect of HDAC in carcinogenesis new therapies were developed. In vitro and in vivo it has been shown that HDAC inhibition could limit growth of cancer cells. In 2006 the HDAC inhibitor (HDACi) suberoylanilide hydroxamic acid (SAHA) was first approved for therapy for cutaneous T-cell lymphoma. Actually different HDACi are investigated in different types of cancers. In this study the expression of the isoforms HDAC1, 2 and 3 in breast cancer was analyzed and correlated with relevant clinicopathological parameters. Furthermore, we examined a potential prognostic impact of the expression of these proteins to identificate a subgroup who might have better benefit of HDACi. Methods: A tissue micro array (TMA) was constructed by formalin-fixed paraffin embedded (FFPE) tissue samples from 238 patients with primary invasive breast cancer diagnosed in the years from 1985 - 1999 in the institute of pathology of Charité University hospital. An immunhistochemical staining of HDAC1, 2 and 3 was done. Finally the slides were digitized and evaluated by virtual microscopy. Results: HDAC1 showed strong expression in 68 (32,7%), intermediate expression in 69 (33,2%) and low expression in 71 (34,1%) cases. For HDAC2 strong expression could be observed in 51 (24,1%), intermediate expression in 69 (32,5%) and low expression in 92 (43,4%) cases. HDAC3 was strongly expressed in 71 (31,7%), intermediately expressed in 73 (32,6%) and low expressed in 80 (35,7%) samples. HDAC1 was highly expressed in hormone receptor positive tumors (n=203; p

PURPOSE: To evaluate how the association between body size and breast cancer risk varies by tumor receptor subtype, host factors, and other exposures among women in the California Teachers Study cohort. METHODS: Among 52,642 postmenopausal women, 2,321 developed invasive breast cancer with known estrogen- and progesterone-receptor status (1,652 ER+PR+, 338 ER+PR-, and 312 ER-PR-) between 1995 and 2007. In a subset of 35,529 with waist circumference data, 1,377 developed invasive breast cancer with known ERPR status (991 ER+PR+, 208 ER+PR-, 169 ER-PR-) between 1997 and 2007. Multivariate Cox regression was performed to estimate relative risks (RR) and 95% confidence intervals (CI). RESULTS: Obesity, adult weight gain of ≥40 pounds, greater abdominal adiposity, and greater height increased the risk of ER+PR+ breast cancer. The increased risk associated with postmenopausal obesity was limited to those who did not use hormone therapy (HT) at cohort entry (RR = 1.37; 95% CI, 1.05-1.78 for BMI ≥ 30 vs.

Item does not contain fulltext Invasive lobular breast cancer (ILC) is less common than invasive ductal breast cancer (IDC) and appears to have a distinct biology. Inconsistent findings regarding disease-free survival (DFS) are probably due to the fact that histologic type is related to hormone receptor status. This study aims to determine whether the type of the primary breast cancer histology is an independent prognostic factor for DFS, the risk pattern of loco-regional recurrences and distant metastases (DM), and whether it is a prognostic factor for the site of DM. All Dutch women diagnosed between 2003 and 2005 with ILC (n = 2,949) or IDC (n = 22,378) were selected from the Netherlands Cancer Registry. DFS was assessed using proportional hazard regression analysis. Compared to patients with IDC, those with ILC were significantly older and more likely to have more than three positive lymph nodes and have larger, better differentiated, more multifocal, and hormone receptor positive tumors (all P < 0.001). ILC was more likely to metastasize to the gastrointestinal organs and bones and less likely to the lung, central nervous system, and lymph nodes. Within the ER+PR+ and ER+PR- subgroups ILC was still more likely to metastasize to gastrointestinal organs and less likely to the lung. The timing of recurrence was correlated to hormone receptor status, independent of histological type. Highest risks were observed among ER-PR- patients within 2 years of surgery. Multivariable analysis showed that histological type is not an independent significant prognostic factor of DFS for the first 3 years post-surgery and thereafter (3 years HR 1.07, 95 % CI 0.88-1.30). Histological type should not be considered an important prognostic factor for the risk and risk pattern of recurrences. 01 augustus 2012