Parity-related molecular signatures and breast cancer subtypes by estrogen receptor status.

Melissa Rotunno,Jonine Figueroa,Mark E Sherman,Tyisha Williams,Xuezheng Sun,Sallie Smith Schneider,Melissa A Troester,Xiaohong R Yang,Paul Meltzer,D Joseph Jerry,Montserrat Garcia-Closas

doi:10.1186/bcr3689

Abstract

IntroductionRelationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Characterizing parity-related gene expression patterns in normal breast and breast tumor tissues may improve understanding of the biological mechanisms underlying this complex pattern of risk.MethodsWe developed a parity signature by analyzing microRNA microarray data from 130 reduction mammoplasty (RM) patients (54 nulliparous and 76 parous). This parity signature, together with published parity signatures, was evaluated in gene expression data from 150 paired tumors and adjacent benign breast tissues from the Polish Breast Cancer Study, both overall and by tumor estrogen receptor (ER) status.ResultsWe identified 251 genes significantly upregulated by parity status in RM patients (parous versus nulliparous; false discovery rate = 0.008), including genes in immune, inflammation and wound response pathways. This parity signature was significantly enriched in normal and tumor tissues of parous breast cancer patients, specifically in ER-positive tumors.ConclusionsOur data corroborate epidemiologic data, suggesting that the etiology and pathogenesis of breast cancers vary by ER status, which may have implications for developing prevention strategies for these tumors.

Highlights

Relationships of parity with breast cancer risk are complex
The fresh whole-breast tissue analyzed in Pioneer Valley Life Sciences Institute (PVLSI) reduction mammoplasty (RM), Polish Breast Cancer Study (PBCS) cancer-adjacent normal tissues and SHL core biopsies consisted of both stromal and epithelial tissues, epithelial cells were microdissected in the University of Illinois at Chicago Hospital (UICH) sample and comprised the dominant cell type in tumors from the PBCS
Discovery of parity signature in PVLSI mammoplasty specimens By gene expression profiling analysis of PVLSI samples, we identified 251 upregulated genes associated with parity

Summary

Introduction

Relationships of parity with breast cancer risk are complex. Parity is associated with decreased risk of postmenopausal hormone receptor–positive breast tumors, but may increase risk for basal-like breast cancers and early-onset tumors. Evaluation of molecular heterogeneity of tumors has led to dramatic changes in our conceptualization of breast cancer, which is widely recognized as representing at least five molecular subtypes with distinct clinicopathological characteristics and risk factor profiles [9,15,16,17] This tumor heterogeneity is important in relation to parity because parity and early age at first full-term birth are associated with reduced risk for ER-positive (ER+) or and (ER + or PR+) breast tumors, but they do not seem to reduce, or they may even increase, lifetime risk for ER-negative (ER−), triple-negative (ER − and PR − and HER2−) breast tumors [8,18,19,20,21,22,23]. These findings suggest that parity-related factors may influence breast cancer risk through different molecular pathways in ER + and ER − tumors

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