Abstract

AimTo investigate the cellular and immunophenotypic basis of mammographic density in women at high risk of breast cancer.MethodsMammograms and targeted breast biopsies were accrued from 24 women at high risk of breast cancer. Mammographic density was classified into Wolfe categories and ranked by increasing density. The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERα, ERβ, PgR, HER2, Ki-67, and CD31) slides and correlated to mammographic density.ResultsIncreasing mammographic density was significantly correlated with increased fibrous stroma proportion (rs (22) = 0.5226, p = 0.0088) and significantly inversely associated with adipose tissue proportion (rs (22) = -0.5409, p = 0.0064). Contrary to previous reports, stromal expression of ERα was common (19/20 cases, 95%). There was significantly higher stromal PgR expression in mammographically-dense breasts (p=0.026).ConclusionsThe proportion of stroma and fat underlies mammographic density in women at high risk of breast cancer. Increased expression of PgR in the stroma of mammographically dense breasts and frequent and unexpected presence of stromal ERα expression raises the possibility that hormone receptor expression in breast stroma may have a role in mediating the effects of exogenous hormonal therapy on mammographic density.

Highlights

  • Mammographic density is a strong and independent risk factor for breast cancer, reported to exceed all other risk factors apart from age and the presence of mutations in high penetrance breast cancer predisposition genes such as BRCA1 and BRCA2[1]

  • The histological composition and immunophenotypic profile were quantified from digitized haematoxylin and eosin-stained and immunohistochemically-stained (ERα, ERβ, progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki-67, and CD31) slides and correlated to mammographic density

  • While heritable factors account for approximately 50–60% of the variance in mammographic density[2,3], other determinants including reproductive history and exogenous hormone use, body mass index (BMI), and importantly, tamoxifen treatment influence mammographic density

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Summary

Introduction

Mammographic density is a strong and independent risk factor for breast cancer, reported to exceed all other risk factors apart from age and the presence of mutations in high penetrance breast cancer predisposition genes such as BRCA1 and BRCA2[1]. In the general population, the appearance of mammographic density has been attributed to increased fibroglandular tissue[5,6,7,8], only a small number of high risk patients including BRCA1/2 mutation carriers[9] have been studied, and whether the same observations applies to this group of women more broadly is unknown. There have been few studies of high-risk women where breast tissue was collected specially for the purpose of investigating mammographic density in contrast to tissue collected for other indications. We have investigated the cellular basis of mammographic density in women at high risk of breast cancer defined by established criteria[10] by assessing histological composition. We further undertook immunophenotypic studies to support the genesis of a hypothesis to explain the underlying molecular basis of a change in mammographic density in patients administered hormonal therapy and selective estrogen receptor modulators (SERMs)

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