Amount of stroma is associated with mammographic density and stromal expression of oestrogen receptor in normal breast tissues

Abstract

Following female sex and age, mammographic density is considered one of the strongest risk factors for breast cancer. Despite the association between mammographic density and breast cancer risk, little is known about the underlying histology and biological basis of breast density. To better understand the mechanisms behind mammographic density we assessed morphology, proliferation and hormone receptor status in relation to mammographic density in breast tissues from healthy women. Tissues were obtained from 2012-2013 by ultrasound-guided core needle biopsy from 160 women as part of the Karma (Karolinska mammography project for risk prediction for breast cancer) project. Mammograms were collected through routine mammography screening and mammographic density was calculated using STRATUS. The histological composition, epithelial and stromal proliferation status and hormone receptor status were assessed through immunohistochemical staining. Higher mammographic density was significantly associated with a greater proportion of stromal and epithelial tissue and a lower proportion of adipose tissue. Epithelial expression levels of Ki-67, oestrogen receptor (ER) and progesterone receptor (PR) were not associated with mammographic density. Epithelial Ki-67 was associated with a greater proportion of epithelial tissue, and epithelial PR was associated with a greater proportion of stromal and a lower proportion of adipose tissue. Epithelial ER was not associated with any tissues. In contrast, expression of ER in the stroma was significantly associated with a greater proportion of stroma, and negatively associated with the amount of adipose tissue. High mammographic density is associated with higher amount of stroma and epithelium and less amount of fat, but is not associated with a change in epithelial proliferation or receptor status. Increased expressions of both epithelial PR and stromal ER are associated with a greater proportion of stroma, suggesting hormonal involvement in regulating breast tissue composition.

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

“…In our study, genes, such as GATA3, ERBB4, RET, NAT1, and TFF3, typically more expressed in ER positive tumor samples, were also more expressed in stromal cells from ER positive as compared with ER negative tumors (defined by immunohistochemistry of malignant cells) [20][21][22]. This result may reflect estrogen responsiveness, mediated by ER expression in stromal fibroblasts [23], as well as some degree of contamination of the samples of microdissected stromal cells with malignant cells (ER positive or ER negative). Among the genes more expressed in ER negative tumors, there was HSD17B2, which codes for an enzyme involved in metabolizing androgens and estrogen to less active metabolites, further indicating that the estrogen pathway is not critical in these tumors.…”

Breast density: why all the fuss?

“…In a more recent casecontrol study from the BCSC, MD was the most prevalent risk factor and had the largest effect on the population attributable risk proportion; the authors estimated that roughly 39% of premenopausal and 26% of postmenopausal breast cancers could be averted if all women with heterogeneously or extremely dense breasts shifted to scattered fibroglandular breast density (64). Some groups have found increased stromal expression of ER and epithelial or stromal expression of PR in dense tissue samples from women at population risk or increased risk (80,81). Laboratory studies using mouse models and human tissue xenografts have shown that tamoxifen treatment promotes remodelling of stroma to a tumour-inhibitory phenotype, with reduced extracellular matrix turnover and decreased stromal tissue (82,83).…”

Review of quantitative multiscale imaging of breast cancer

“…46,169,171,172 The primary use of QHP in QMIB is to validate imaging modalities at other spatial scales by diagnosing pathology, but there are many secondary uses. One use of multiscale QHP is quantifying the biology of MD in terms of the PMD of the whole breast 41,[173][174][175][176][177][178][179][180] or the local density (LD) of tissue. [181][182][183][184][185] The relative proportion of highly x-ray attenuating, radio dense, fibroglandular tissue to adipose tissue (MD) is an important risk factor in breast cancer, with up to a 4-to 6-fold difference in risk between women with high and low MD women.…”

“…There are no strong divergent trends according to current literature. 174 However, future differences may be discovered as multiscale QHP spreads and facilitates a greater number of studies.…”