Abrupt involution induces inflammation, estrogenic signaling, and hyperplasia linking lack of breastfeeding with increased risk of breast cancer

Abstract

Background A large collaborative analysis of data from 47 epidemiological studies concluded that longer duration of breastfeeding reduces the risk of developing breast cancer. Despite the strong epidemiological evidence, the molecular mechanisms linking prolonged breastfeeding to decreased risk of breast cancer remain poorly understood. Methods We modeled two types of breastfeeding behaviors in wild type FVB/N mice: (1) normal or gradual involution of breast tissue following prolonged breastfeeding and (2) forced or abrupt involution following short-term breastfeeding. To accomplish this, pups were gradually weaned between 28 and 31 days (gradual involution) or abruptly at 7 days postpartum (abrupt involution). Mammary glands were examined for histological changes, proliferation, and inflammatory markers by immunohistochemistry. Fluorescence-activated cell sorting was used to quantify mammary epithelial subpopulations. Gene set enrichment analysis was used to analyze gene expression data from mouse mammary luminal progenitor cells. Similar analysis was done using gene expression data generated from human breast samples obtained from parous women enrolled on a tissue collection study, OSU-2011C0094, and were undergoing reduction mammoplasty without history of breast cancer. Results Mammary glands from mice that underwent abrupt involution exhibited denser stroma, altered collagen composition, higher inflammation and proliferation, increased estrogen receptor α and progesterone receptor expression compared to those that underwent gradual involution. Importantly, when aged to 4 months postpartum, mice that were in the abrupt involution cohort developed ductal hyperplasia and squamous metaplasia. Abrupt involution also resulted in a significant expansion of the luminal progenitor cell compartment associated with enrichment of Notch and estrogen signaling pathway genes. Breast tissues obtained from healthy women who breastfed for < 6 months vs ≥ 6 months showed significant enrichment of Notch signaling pathway genes, along with a trend for enrichment for luminal progenitor gene signature similar to what is observed in BRCA1 mutation carriers and basal-like breast tumors. Conclusions We report here for the first time that forced or abrupt involution of the mammary glands following pregnancy and lack of breastfeeding results in expansion of luminal progenitor cells, higher inflammation, proliferation, and ductal hyperplasia, a known risk factor for developing breast cancer. Electronic supplementary material The online version of this article (10.1186/s13058-019-1163-7) contains supplementary material, which is available to authorized users.

Postpartum Involution and Cancer: An Opportunity for Targeted Breast Cancer Prevention and Treatments?

“…The latter observation in mice that abrupt cessation promoted the expression of estrogen and progesterone receptors is in agreement with the protective effect of breastfeeding against ER+ breast cancer in women (23,37). The authors also reported ductal hyperplasia four months postpartum in mice where lactation was abruptly interrupted (113). It is currently unknown whether this holds true in humans.…”

“…This finding is consistent with the role of PAPP-A in involution and the importance of the STCs to inhibit PAPP-A activity, since PAPP-A is known to be induced by inflammatory cytokines such as IL-6, TNF, IL-1, IL-4, and TGF- (112). Abrupt cessation of lactation was also associated with increased cellular proliferation and deposition of collagen as well as expansion of the luminal progenitor cells in the mammary gland compared to mice where cessation of lactation was gradual (113). The latter observation in mice that abrupt cessation promoted the expression of estrogen and progesterone receptors is in agreement with the protective effect of breastfeeding against ER+ breast cancer in women (23,37).…”

“…Inflammation 85,86 Immune tolerance 60 Lymphangiogenesis 44,51,60 <5 Parous 44,45,72 Collagen 45,56,72,108,113 PAPP-A 104,107,108 cleavage SEMA7A 51NSAIDs 55 STC-1 110 STC-2 109 IGFBP-5 94,[100][101][102][103] IGF signaling 94 DDR2 signaling 108…”

Characterization of weaning-induced breast involution in women: implications for young women’s breast cancer

“…Based on recently published mouse studies, our data showing heightened immune cell infiltrate and cell death in healthy postweaning breast tissue might also be unanticipated. Specifically, in several mouse models, longer duration of lactation and more gradual weaning are found to protect against breast cancer [49][50][51] . These gradual weaning studies suggest that rodent models of abrupt weaning may not mirror the breast involution processes in humans, who may be more likely to participate in gradual weaning.…”

Aspirin use and risk of breast cancer in African American women

“…Inverse associations of aspirin with ER− and TN disease may therefore be driven by its anti-inflammatory effects rather than hormone-dependent mechanisms [ 40 , 41 ]. Indeed, our observation of stronger associations among women 50 years and older, those with higher central adiposity, and parous women, groups with higher levels of systemic inflammation [ 42 – 46 ], is supportive of this theory; however, we were not able to evaluate potential mechanisms directly in this study.…”