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Background High levels of tumor-infiltrating lymphocytes (TILs) are associated with improved prognosis and response to therapy in patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Purpose This study investigated the associations between TIL levels and magnetic resonance imaging (MRI) findings in patients with estrogen receptor (ER)-negative HER-2 positive breast cancer. Material and Methods This study included 110 consecutive patients with surgically confirmed ER-negative HER2-positive breast cancers who underwent preoperative MRI from January to December 2015. Images of all lesions were reviewed in accordance with the BI-RADS lexicon by radiologists blinded to clinicopathologic findings. Tumor kinetic features were acquired by computer-aided diagnosis (CAD). Patients were divided into three TIL groups: low (50%). Associations between TIL levels and clinicopathologic and imaging features were evaluated; independent predictors of high and low TIL were identified by multiple logistic regression analysis. Results The 110 patients included 29 (26.4%) with low, 45 (40.9%) with intermediate, and 36 (32.7%) with high TIL levels. Multiple logistic regression analysis showed that older age (odds ratio [OR] = 1.08; P = 0.017), high peak enhancement (OR = 1.01; P = 0.019), positive CK5/6 (OR = 4.36; P = 0.024), and low Ki-67 (OR = 14.29; P = 0.037) were significantly associated with low TILs; low peak enhancement (OR = 1.01; P = 0.020) was significantly associated with high TILs. Conclusion MRI features may predict TIL levels in patients with ER-negative HER-2 positive breast cancer, enhancing the ability to diagnose and treat these patients.

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 – from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.

peer-reviewed When breast cancer progresses to a metastatic stage, survival rates decline rapidly and it is considered incurable. Thus, deciphering the critical mechanisms of metastasis is of vital importance to develop new treatment options. We hypothesize that studying the proteins that are newly synthesized during the metastatic processes of migration and invasion will greatly enhance our understanding of breast cancer progression. We conducted a mass spectrometry screen following bioorthogonal noncanonical amino acid tagging to elucidate changes in the nascent proteome that occur during epidermal growth factor stimulation in migrating and invading cells. Annexin A2 was identified in this screen and subsequent examination of breast cancer cell lines revealed that Annexin A2 is specifically upregulated in estrogen receptor negative (ER-) cell lines. Furthermore, siRNA knockdown showed that Annexin A2 expression promotes the proliferation, wound healing and directional migration of breast cancer cells. In patients, Annexin A2 expression is increased in ER- breast cancer subtypes. Additionally, high Annexin A2 expression confers a higher probability of distant metastasis specifically for ER- patients. This work establishes a pivotal role of Annexin A2 in breast cancer progression and identifies Annexin A2 as a potential therapeutic target for the more aggressive and harder to treat ER- subtype.

Previous studies revealed that PBX1 ranked the third in the differentially expressed genes about development and progression of breast cancer (BC). Nevertheless, the role of PBX1 contributing to progression of BC has been unevaluated. Here, on the basis of ONCOMINE and GOBO databases, we compared BC samples with normal controls about the expression of PBX1 in various types of cancers, as well as their related expression levels in cancer cell lines by Cancer Cell Line Encyclopedia (CCLE) analysis. It was also found that, when compared with normal controls, PBX1 was markedly higher expressed not only in BC samples but also in BC cell lines, and coexpressed with EMP2 by ONCOMINE and CCLE coexpression analysis, which was also expressed higher in BC samples and BC cell lines similarly. According to Kaplan-Meier plotter, we further explored the prognostic functions of PBX1 and EMP2 in different molecular subtypes of BC, respectively. We demonstrated that overexpression of PBX1 mRNA was correlated with worse survival in luminal B subtype BC, whereas increased EMP2 expression was associated with shorter relapse-free survival in estrogen receptor (ER)-negative patients. Combining with previous studies, we could make a conclusion that coexpression of PBX1 and EMP2 predicts poor prognosis in ER-negative BC, which could be effective biomarkers for BC.

Hidradenocarcinoma is an extremely rare cutaneous skin carcinoma which arise from the sweat gland. There are several report about potential targets in this rare disease including estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2). A 53-year-old man who presented with a slowly growing mass on the left thumb which was pathologically confirmed of HER2 negative, ER negative hidradenocarcinoma. At the time of presentation, the patient had metastatic lesions to lung and axillary lymph nodes. The patient received several lines of palliative chemotherapy and radiotherapy, but died of the disease progression. We identified TP53 G245S mutation in both primary tumor specimen and cell-free based targeted sequencing. Herein, we report on a very rare case of metastatic hidradenocarcinoma with TP53 G245S mutation but no other treatable targets from clinical sequencing, which pursued an aggressive clinical course.

Background: Cancer immunotherapy is revolutionizing treatment today. While MBC with estrogen receptor positive (ER+) tumors, responding or stabilizing after first line chemotherapy, may have a benefit from a maintenance endocrine therapy combined with the monoclonal antibody bevacizumab, no option exists for ER- patients. In the past, we have shown, that a combination of 13-cis retinoic acid (RA) and interleukin-2 (IL-2) was able to improve the immune function [enhancing lymphocyte and natural killer cell (NK) counts, and CD4+/CD8+ ratio] of cancer patients who had had a clinical benefit from chemotherapy (Clin Cancer Res 2001;7:1251). With the aim of improving the immune function which eventually would lead to improvement of progression free survival (PFS) and overall survival (OS), patients with ER- LA or MBC, with a clinical benefit from chemotherapy, were treated with a combination of IL-2 and RA. Methods: Eligible patients with ER-, LA or MBC, and no evidence of progression after induction chemotherapy received the following immunotherapy: IL-2, (1.8 M UI ), and oral RA (0.5 mg/kg), 5 days/week, 3 weeks/month for 1 year. Therapy was continued, with intermittent schedule until progression. Primary endpoints were the differences in lymphocyte , natural killer cell (NK) counts, and CD4+/CD8+ ratio, secondary end points were progression free survival (PFS), overall survival (OS) and toxicity. Results: From 12/1996 to 04/2009, 74 patients with ER-, LA (49%) or MBC (51%) were entered into the study. Median age was 55 years (range 31-75), 31% of patients were pre-menopausal. Each patient had received a median of 11 courses of first line and salvage chemotherapy regimens (total 850 courses). In addition, 31 patients had received high-dose chemotherapy with peripheral blood progenitor cell transplantation. Disease sites were as follows: soft tissue 54%, viscera 28%, bones 18%. After a median follow-up of 118 months (range 84-232), a total of 374 courses of immunotherapy were delivered. No WHO grade 3 or 4 toxicity was observed; grade 2 cutaneous toxicity and autoimmune reactions occurred in 19% and 16% of patients, respectively. A Statistically significant improvement with respect to baseline values was observed in the number of lymphocytes (p Citation Format: Recchia F, Candeloro G, Rea S. Maintenance immunotherapy in estrogen receptor negative (ER-) locally advanced (LA) and/or metastatic breast cancer (MBC). Long-term follow-up of a phase II study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P6-16-06.

// Allyson C. Espinal 1, * , Dan Wang 2, * , Li Yan 2 , Song Liu 2 , Li Tang 3 , Qiang Hu 2 , Carl D. Morrison 4 , Christine B. Ambrosone 4 , Michael J. Higgins 1, # , Lara E. Sucheston-Campbell 5, 6, # 1 Department of Molecular and Cell Biology, Roswell Park Cancer Institute, Buffalo NY, USA 2 Department of Biostatistics, Roswell Park Cancer Institute, Buffalo, NY, USA 3 Department of Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo, NY, USA 4 Department of Pathology, Roswell Park Cancer Institute, Buffalo, NY, USA 5 College of Pharmacy, The Ohio State University, Columbus, OH, USA 6 Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH, USA * These authors contributed jointly as first authors # These authors contributed jointly as senior authors Correspondence to: Lara E. Sucheston-Campbell, email: sucheston-campbell.1@osu.edu Michael J. Higgins, email: Michael.Higgins@roswellpark.org Keywords: DNA methylation/epigenetics, breast cancer, estrogen receptor negative Received: May 27, 2016 Accepted: January 10, 2017 Published: January 19, 2017 ABSTRACT Background: DNA from archival formalin-fixed and paraffin embedded (FFPE) tissue is an invaluable resource for genome-wide methylation studies although concerns about poor quality may limit its use. In this study, we compared DNA methylation profiles of breast tumors using DNA from fresh-frozen (FF) tissues and three types of matched FFPE samples. Results: For 9/10 patients, correlation and unsupervised clustering analysis revealed that the FF and FFPE samples were consistently correlated with each other and clustered into distinct subgroups. Greater than 84% of the top 100 loci previously shown to differentiate ER+ and ER– tumors in FF tissues were also FFPE DML. Weighted Correlation Gene Network Analyses (WCGNA) grouped the DML loci into 16 modules in FF tissue, with ~85% of the module membership preserved across tissue types. Materials and Methods: Restored FFPE and matched FF samples were profiled using the Illumina Infinium HumanMethylation450K platform. Methylation levels (β-values) across all loci and the top 100 loci previously shown to differentiate tumors by estrogen receptor status (ER+ or ER−) in a larger FF study, were compared between matched FF and FFPE samples using Pearson's correlation, hierarchical clustering and WCGNA. Positive predictive values and sensitivity levels for detecting differentially methylated loci (DML) in FF samples were calculated in an independent FFPE cohort. Conclusions: FFPE breast tumors samples show lower overall detection of DMLs versus FF, however FFPE and FF DMLs compare favorably. These results support the emerging consensus that the 450K platform can be employed to investigate epigenetics in large sets of archival FFPE tissues.

Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

Risk factors for breast cancer are often confusing and contradictory. Discrepancies are likely due to different subtypes having divergent risk factors. An important distinction between breast cancer subtypes is hormone-receptor status. Compared to women diagnosed with estrogen receptor positive (ER+) breast cancer, those with estrogen receptor negative (ER−) tumors are usually diagnosed at a younger age and have a higher mortality [1]. Few studies have attempted to explain ‘why’ breast cancer subtypes have different risk factors.

Despite the controversies, estrogen receptor-negative/progesterone receptor-positive (ER-/PR+) breast cancers have a reported incidence of 1% to 4%. These tumors are less well defined, and it is unclear whether ER-/PR+ represents a distinct subtype. Thus, we analyzed 5374 consecutive breast cancers to characterize the clinicopathological features of this underrecognized subset of tumors. The ER-/PR+ tumors, constituting 2.3% of the total, were mostly high grade and significantly seen in younger patients and African American women when compared with the ER+/PR+ and ER+/PR- groups, but similar to that of ER-/PR- phenotype (P.0001). A significantly prolonged relapse-free survival (RFS) was associated with the ER+/PR+ subtype when compared with the ER+/PR- (P = .0002) or ER-/PR+ (P = .0004) tumors, whereas all 3 groups showed a superior outcome to that of the ER-/PR- phenotype. In the subset of patients receiving endocrine therapy, those with ER+/PR+ tumors had a significantly prolonged RFS (P = .001) and disease-specific survival (P = .005) when compared with the group with an ER+/PR- phenotype, but did not significantly differ from those with ER-/PR+ tumors. No significant survival advantage was found between the ER+/PR- and ER-/PR+ tumors in any group of patients analyzed. Furthermore, a higher PR expression was associated with a favorable RFS and disease-specific survival in the patients with ER-/PR+ tumors. Therefore, the ER-/PR+ tumors demonstrate a similar, if not higher than, response rate to endocrine therapy when compared with the ER+/PR- tumors and thus are important to identify. Routine PR testing remains necessary in assisting clinical decision making in the pursuit of precision medicine.

Biomarkers for cancer are essential for diagnosis, prognosis and for predicting the response to specific treatments. Each biomarker has a degree of specificity and sensitivity. For example, estrogen receptors are good biomarkers for breast carcinomas, but there are breast cancers that are estrogen receptor negative, and there are other tumors, e.g., ovarian cancers, which are estrogen receptor positive. As a limited number of cancer biomarkers are specific and sensitive enough for the universal detection of these diseases, there is a constant quest for biomarkers capable of detecting cancers earlier, more reliably and less invasively. While searching for biomarkers using techniques routinely available or developed from related methods in biomedicine, interdisciplinary research offers novel, unique approaches to fulfill this need. One such approach is the application of isotopic techniques originating in Earth Sciences to biomedical studies, in the search of these all-important biomarkers.

This study proposes an algorithm for predicting breast cancer prognosis based on genetic network. We identify prognosis-specific network using gene expression data and PPI(protein-protein interaction) data. To acquire the network, we calculate Pearson's correlation coefficient(PCC) between genes in all PPI pairs ∙제1저자 : 황유현 ∙제2저자 : 오민 ∙교신저자 : 윤영미 ∙투고일 : 2014. 11. 12, 심사일 : 2014. 12. 31, 게재확정일 : 2015. 1. 29. * 가천대학교 컴퓨터공학과(Dept. of Computer Engineering, Gachon University) **가천대학교 컴퓨터공학과 교수(교신저자)(Dept. of Computer Engineering, Gachon University) ※이 논문은 정부(교육과학기술부)의 재원으로 한국연구재단의 기초연구사업 지원을 받아 수행된 것임(NRF-2010-0008639). 138 Journal of The Korea Society of Computer and Information February 2015 using gene expression data. We develop a prediction model for breast cancer patients with estrogen-receptor-negative using the network as a classifier. We compare classification performance of our algorithm with existing algorithms on independent data and shows our algorithm is improved. In addition, we make an functionality analysis on the genes in the prognosis-specific network using GO(Gene Ontology) enrichment validation. ▸

The estrogen receptor α (ER) and the progesterone receptor (PgR) are one of the most important prognostic and predictive immunohistochemical markers in breast cancer. Breast cancers may express various profiles of hormone receptors: ER(+)/PgR(+), ER(-)/PgR(-), ER(+)/PgR(-) and ER(-)/PgR(+). The existence of the latter profile is a matter of controversy since PgR expressions is induced by ER-dependent pathways in breast cancer cells. One of the most extensively propagated hypotheses trying to explain the origin of ER(-)/PgR(+) breast cancers claims that they are technical artifacts dependent on the immunohistochemical procedure. On the other hand, in recent years there is a growing body of evidence, suggesting that such cancers create a unique group with distinct molecular and clinical features. In the following review, we present background theories on the ER(-)/PgR(+) breast cancer origin and their epidemiological and clinicopathological characteristics, including the predictive and prognostic significance of these rare tumors.

Estrogen receptor-positive (ER+) and ER-negative (ER-) subtypes of breast cancer have distinct clinical outcomes because they respond differentially to endocrine therapies. We aimed to comprehensively analyze differentially expressed microRNA (miRNAs), long non-coding RNAs (lncRNAs) and mRNAs in different ER subtypes as well as to identify prognosis-related RNAs. The expression levels of miRNAs, lncRNAs, and mRNAs between breast cancer and normal samples were compared using data from The Cancer Genome Atlas database. Differentially expressed miRNAs, lncRNAs and mRNAs between ER+ and ER- samples were also screened. An ER subtype-related miRNA-lncRNA-mRNA network was constructed. lncRNAs and mRNAs in this network were further subjected to an analysis of their associations with patient prognosis. Sets of differentially expressed miRNAs, lncRNAs, and miRNAs between breast cancer and normal samples were identified among which 14 miRNAs, 78 lncRNAs, and 475 mRNAs were differentially expressed between ER subtypes. Relationships between these RNAs were analyzed. The resultant ER subtype-related miRNA-lncRNA-mRNA network consisted of 14 nodes, among which LINC0092 and chromosome 2 open reading frame 71 (C2orf71) were correlated with better prognosis of breast cancer. LINC0092 was co-expressed with SFRP1 and RGMA and regulated by hsa-miR-449a and hsa-miR-452-5p. C2orf71 was co-expressed with LINC00511 and regulated by hsa-miR-184. Cross-talk among differentially expressed miRNAs, lncRNAs, and miRNAs may be an important feature in ER+ and ER- subtypes of breast cancer. LINC0092 and C2orf71, two of these cross-talking RNAs, may serve as novel prognostic predictor of breast cancer because of their close associations with prognosis.

BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.

PURPOSE: Isolated locoregional recurrence (ILRR) predicts a high risk of developing breast cancer distant metastases and death. The Chemotherapy as Adjuvant for LOcally Recurrent breast cancer (CALOR) trial investigated the effectiveness of chemotherapy (CT) after local therapy for ILRR. A report at 5 years of median follow-up showed significant benefit of CT for estrogen receptor (ER)–negative ILRR, but additional follow-up was required in ER-positive ILRR. PATIENTS AND METHODS: CALOR was an open-label, randomized trial for patients with completely excised ILRR after unilateral breast cancer. Eligible patients were randomly assigned to receive CT or no CT and stratified by prior CT, hormone receptor status, and location of ILRR. Patients with hormone receptor–positive ILRR received adjuvant endocrine therapy. Radiation therapy was mandated for patients with microscopically involved margins, and anti–human epidermal growth factor receptor 2 therapy was optional. End points were disease-free survival (DFS), overall survival, and breast cancer-free interval. RESULTS: From August 2003 to January 2010, 162 patients were enrolled: 58 with ER-negative and 104 with ER-positive ILRR. At 9 years of median follow-up, 27 DFS events were observed in the ER-negative group and 40 in the ER-positive group. The hazard ratios (HR) of a DFS event were 0.29 (95% CI, 0.13 to 0.67; 10-year DFS, 70% v 34%, CT v no CT, respectively) in patients with ER-negative ILRR and 1.07 (95% CI, 0.57 to 2.00; 10-year DFS, 50% v 59%, respectively) in patients with ER-positive ILRR (P(interaction) = .013). HRs were 0.29 (95% CI, 0.13 to 0.67) and 0.94 (95% CI, 0.47 to 1.85), respectively, for breast cancer-free interval (P(i)(nteraction) = .034) and 0.48 (95% CI, 0.19 to 1.20) and 0.70 (95% CI, 0.32 to 1.55), respectively, for overall survival (P(interaction) = .53). Results for the three end points were consistent in multivariable analyses adjusting for location of ILRR, prior CT, and interval from primary surgery. CONCLUSION: The final analysis of CALOR confirms that CT benefits patients with resected ER-negative ILRR and does not support the use of CT for ER-positive ILRR.

In a meta-analysis published by myself and co-authors, we report differences in the life history risk factors for estrogen receptor negative (ER-) and estrogen receptor positive (ER+) breast cancers. Our meta-analysis did not find the association of ER- breast cancer risk with fast life history characteristics that Hidaka and Boddy suggest in their response to our article. There are a number of possible explanations for the differences between their conclusions and the conclusions we drew from our meta-analysis, including limitations of our meta-analysis and methodological challenges in measuring and categorizing estrogen receptor status. These challenges, along with the association of ER+ breast cancer with slow life history characteristics, may make it challenging to find a clear signal of ER- breast cancer with fast life history characteristics, even if that relationship does exist. The contradictory results regarding breast cancer risk and life history characteristics illustrate a more general challenge in evolutionary medicine: often different sub-theories in evolutionary biology make contradictory predictions about disease risk. In this case, life history models predict that breast cancer risk should increase with faster life history characteristics, while the evolutionary mismatch hypothesis predicts that breast cancer risk should increase with delayed reproduction. Whether life history tradeoffs contribute to ER- breast cancer is still an open question, but current models and several lines of evidence suggest that it is a possibility.

Objective: The purpose of the current study is to understand the clinicopathological implications of redox proteins in association with androgen receptor (AR) and HER-2 status in estrogen receptor (ER)-negative breast cancers through evaluation of the expression patterns of redox proteins, such as catalase, thioredoxin reductase (TxNR), glutathione S-transferase π (GSTπ), thioredoxin interacting protein (TxNIP), and manganese superoxide dismutase (MnSOD). Methods: Two hundred cases of ER-negative breast cancer samples were collected as a tissue microarray. Immunohistochemical staining was done for redox-related proteins, after which the resulting data set was organized by AR and HER-2 status. Results: The redox proteins that had a significant association with AR and HER-2 status were tumoral catalase (p < 0.001) and stromal GSTπ (p < 0.001). Tumoral catalase was least expressed in the AR-/HER-2- group, while stromal GSTπ was least expressed in both the AR+/HER-2- and the AR-/HER-2- groups. Stromal GSTπ was highly expressed in HER-2 positive groups (p < 0.001). Stromal GSTπ negativity and tumoral MnSOD positivity were associated with a shorter disease-free survival (p = 0.041 and p = 0.007, respectively) in univariate analysis. Conclusion: ER-negative breast cancers showed different expressions of redox-related proteins according to AR and HER-2 status. Catalase expression was high in AR-negative groups, while stromal GSTπ expression was high in HER-2-positive groups.

$\textbf{Background:}$ Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes $\textit{BRCA1}$ or $\textit{BRCA2}$. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. $\textbf{Methods:}$ We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through populationbased GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female $\textit{BRCA1}$ and 8211 $\textit{BRCA2}$ carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. $\textbf{Results:}$ The PRS for ER-negative BC displayed the strongest association with BC risk in $\textit{BRCA1}$ carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, $P$ = 8.2 $\times$ 10$^{-53}$). In $\textit{BRCA2}$ carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, $P$ = 7.2 $\times$ 10$^{-20}$). The OC PRS was strongly associated with OC risk for both $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom AR deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for $\textit{BRCA2}$ carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. $\textbf{Conclusions:}$ BC and OC PRS are predictive of cancer risk in $\textit{BRCA1}$ and $\textit{BRCA2}$ carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management., Cancer Research UK

This is a pre-copyedited, author-produced version of an article accepted for publication in Annals of Oncology following peer review. The version of record Chajès, V., Assi, N., Biessy, C., Ferrari, P., Rinaldi, S., Slimani, N., ... Romieu, I. (2017). A prospective evaluation of plasma phospholipid fatty acids and breast cancer risk in the EPIC study. Annals of Oncology, 28(11), 2836-2842. https://doi.org/10.1093/annonc/mdx482, is available online at: https://doi.org/10.1093/annonc/mdx482. Background: Intakes of specific fatty acids have been postulated to impact breast cancer risk but epidemiological data based on dietary questionnaires remain conflicting. Materials and methods: We assessed the association between plasma phospholipid fatty acids and breast cancer risk in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition study. Sixty fatty acids were measured by gas chromatography in pre-diagnostic plasma phospholipids from 2982 incident breast cancer cases matched to 2982 controls. Conditional logistic regression models were used to estimate relative risk of breast cancer by fatty acid level. The false discovery rate (q values) was computed to control for multiple comparisons. Subgroup analyses were carried out by estrogen receptor (ER) and progesterone receptor expression in the tumours. Results: A high level of palmitoleic acid [odds ratio (OR) for the highest quartile compared with the lowest OR (Q4–Q1) 1.37; 95% confidence interval (CI), 1.14–1.64; P for trend = 0.0001, q value = 0.004] as well as a high desaturation index (DI16) (16:1n–7/16:0) [OR (Q4–Q1), 1.28; 95% C, 1.07–1.54; P for trend = 0.002, q value = 0.037], as biomarkers of de novo lipogenesis, were significantly associated with increased risk of breast cancer. Levels of industrial trans-fatty acids were positively associated with ER-negative tumours [OR for the highest tertile compared with the lowest (T3–T1)=2.01; 95% CI, 1.03–3.90; P for trend = 0.047], whereas no association was found for ER-positive tumours (P-heterogeneity =0.01). No significant association was found between n-3 polyunsaturated fatty acids and breast cancer risk, overall or by hormonal receptor. Conclusion: These findings suggest that increased de novo lipogenesis, acting through increased synthesis of palmitoleic acid, could be a relevant metabolic pathway for breast tumourigenesis. Dietary trans-fatty acids derived from industrial processes may specifically increase ER-negative breast cancer risk.

As a component of NURD histone deacetylase complex, ZIP serves as a tumor suppressor gene in the development of breast tumors. However, whether it takes part in chemotherapy resistance remains poorly defined. In the present study, we reported that ZIP enhanced the response to SERM chemotherapy in ER-negative cells. Overexpression of ZIP suppressed EGFR expression level and restored ERalpha protein level in cells resistant to Tamoxifen. In vivo data confirmed those in vitro findings.

e12544Background: Recent studies indicated that aryl-hydrocarbon receptor (AHR) modulators - such as omeprazole - decrease breast cancer cell invasion among mice with estrogen receptor negative (ER...

We sought to determine the prevalence of androgen receptor (AR) expression in a predominantly estrogen receptor (ER)-negative subset of breast cancers and delineate the immunohistochemical and clinical associations, including whether AR expression has prognostic significance in ER-negative tumors. We identified 69 ER-negative and 19 ER-positive breast cancer cases with concurrent immunohistochemical prognostic panels (ER, PR, HER-2/neu, Ki-67, and p53); immunohistochemical analysis was performed for AR using standard techniques. Clinical data were extracted from medical records. χ2 tests were used to assess associations between variables. AR was found in 49% (34/69) of ER-negative and 89% (17/19) of ER-positive cases. In ER-negative tumors, AR was associated with increased age ( P = .02), postmenopausal status ( P < .001), tumor grade ( P = .03), tumor size ( P = .03), and HER-2/neu overexpression ( P = .003). In ER-positive tumors, AR was associated with progesterone receptor expression ( P < .03). In univariate analysis of ER-negative tumors, patients with AR-positive tumors had significantly better disease-free survival ( P = .049). AR is expressed in a significant number of ER-negative cases and shows significant associations with important clinical and pathologic prognostic factors.

Genome Wide Association Studies (GWAS) are designed to identify single nucleotide polymorphisms (SNPs) mapping to genomic regions associated with a particular trait or disease. Currently, 19 genomic loci associated with risk for estrogen receptor negative breast cancer have been identified. However, for most of these loci the mechanisms driving susceptibility have remained elusive. The 2p23.2 locus, defined by SNP rs67073037 (p = 4.76 x 10-9), contains 79 SNPs exhibiting genome-wide significant associations as well as four candidate genes: SPDYA, TRMT61B, WDR43, and FAM179A. Post-GWAS functional analysis revealed two candidate causal regulatory elements: an enhancer-like element defined by SNP rs44017214 located in the first intron of the WDR43 gene; and a segment in the 3’-UTR region of WDR43 defined by SNPs rs11680458 and rs11331880 which are predicted to have allele specific binding of non-coding microRNAs miR-548 and miR-376, respectively. We validated allele specific transcription factor binding to rs44017214 using competitive binding of USF1/USF2 to the risk allele in both MCF10A and CAL51 cell lines in Electrophoretic Mobility Shift Assays (EMSA). Additionally, rs44017214 was removed using CRISPR-cas9, and expression of neighboring genes was evaluated by qRT-PCR. No change in expression was found for any gene in a 2 Mb region surrounding the SNP, with the exception of PLB1. This suggests that the enhancer element in the intron of WDR43 has PLB1 as its target. To assess the miRNA binding site impact on WDR43 expression the pMIR-REPORT Luciferase allele-specific vector was co-transfected with miR-141/200, miR548, or miR-376 in MCF10A cells. The rs1131880 allele C in the WDR43 3’-UTR lead to the suppression of luciferase expression by miR-376 compared to the G allele. This study reveals two independent regulatory mechanisms within the 2p23.2 locus; (i) modulation of enhancer activity by allele specific binding of transcription factors USF1/USF2 to rs4401714, and (ii) decreasing the expression of WDR43 through the formation of a miR-376 binding site at the 3’-UTR of the WDR43 gene. Elucidating the functional significance of these common variants in the novel susceptibility loci 2p23.2 furthers our knowledge of the etiology of estrogen receptor negative breast cancer. Citation Format: Carly M. Harro, Gustavo Mendoza-Fandino, Nicholas T. Woods, Xueli Li, Fergus J. Couch, Alvaro N. Monteiro. Two distinct regulatory mechanisms underlie estrogen receptor negative breast cancer susceptibility at the 2p23.2 locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1306. doi:10.1158/1538-7445.AM2017-1306

While epidermal growth factor receptor (EGFR)-targeted therapy has been very promising in a number of human malignancies, to date these targeted biologic agents have not proven effective in breast cancer. However, the EGFR tyrosinase inhibitors have been used indiscriminately against all types of breast tumors, perhaps missing a subpopulation of patients who may be prime candidates for EGFR-targeted therapy. In this communication we propose that patients with estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/HER-2-negative tumors, which currently present a therapeutic challenge for the oncologist, may be the subgroup of breast cancer patients that might benefit from specific EGFR-targeted therapies.