Abstract
BackgroundWomen, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. While BRCA1 carriers frequently develop triple-negative, basal-like, aggressive breast tumors, hormone signaling is important in the genesis of BRCA1 mutant breast cancers. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system.MethodsScaffold-free, multicellular human breast organoids generated from benign breast tissues from non-carrier or BRCA1 mutation carriers were treated in vitro with a stepwise menstrual cycle hormone regimen of estradiol (E2) and progesterone (P4) over the course of 28 days.ResultsBreast organoids exhibited characteristics of the native breast tissue, including expression of hormone receptors, collagen production, and markers of luminal and basal epithelium, and stromal fibroblasts. RNA sequencing analysis revealed distinct gene expression in response to hormone treatment in the non-carrier and BRCA1-mutated organoids. The selective progesterone receptor modulator, telapristone acetate (TPA), was used to identify specifically PR regulated genes. Specifically, extracellular matrix organization genes were regulated by E2+P4+TPA in the BRCA1-mutated organoids but not in the non-carrier organoids. In contrast, in the non-carrier organoids, known PR target genes such as the cell cycle genes were inhibited by TPA.ConclusionsThese data show that BRCA1 mutation influences hormone response and in particular PR activity which differs from that of non-carrier organoids. Our organoid model system revealed important insights into the role of PR in BRCA1-mutated benign breast cells and the critical paracrine actions that modify hormone receptor (HR)-negative cells. Further analysis of the molecular mechanism of BRCA1 and PR crosstalk is warranted using this model system.
Highlights
Women, who carry a germline Breast cancer-associated gene 1 (BRCA1) gene mutation, have a markedly increased risk of developing breast cancer during their lifetime
Information regarding the type of surgery, age, menopause status, and BRCA1 mutation type is provided in Additional file 8: Table S1
Organoids derived from breast tissues from reduction mammoplasty (RM) which are BRCA1 wildtype (WT) will be referred to as ānon
Summary
Women, who carry a germline BRCA1 gene mutation, have a markedly increased risk of developing breast cancer during their lifetime. We investigated the hormone response in BRCA1-mutated benign breast tissue using an in vitro organoid system. Women who carry a germline mutation in the breast cancer-. 10ā15% of luminal epithelial cells express the hormone receptors (HRs), estrogen receptor (ER), and progesterone receptor (PR) [5]. ER and PR in the luminal epithelial cells drive the biological changes of the breast in response to estrogen (E2) and progesterone (P4) during each menstrual cycle. It is evident that hormone action in the mammary gland involves intricate paracrine actions between cells for such changes to occur throughout the breast
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