Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation

Abstract

Breast cancer developed in familial BRCA1 mutation carriers bears striking similarities to sporadic basal-like breast tumors. The mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that the deletion of p18(Ink4c) (p18), an inhibitor of G1 cyclin Ds-dependent CDK4 and CDK6, stimulates mammary luminal progenitor cell proliferation and leads to spontaneous luminal tumor development. We report here that germline mutation of Brca1 in p18-deficient mice blocks the increase of luminal progenitor cells, impairs luminal gene expression and promotes malignant transformation of mammary tumors. Instead of the luminal mammary tumors developed in p18 single-mutant mice, mammary tumors developed in the p18;Brca1 mice, similar to breast cancer developed in familial BRCA1 carriers, exhibited extensive basal-like features and lost the remaining wild-type allele of Brca1. These results reveal distinct functions of the RB and BRCA1 pathways in suppressing luminal and basal-like mammary tumors, respectively. These results also suggest a novel mechanism--causing luminal-to-basal transformation--for the development of basal-like breast cancer in familial BRCA1 carriers and establish a unique mouse model for developing therapeutic strategies to target both luminal and basal-like breast cancers.

Solitary Hypothalamus Triple Negative Metastasis from Luminal: A Primary Breast Carcinoma

“…Indeed, the receptor status of the metastasis may be more predictive of response to therapy. One small study showed that, although 74% of patients with ER-positive primary tumours whose recurrent tumours retained ER expression responded to endocrine therapy, only 12% of patients with ER-positive primaries and ER-negative metastases likewise responded [8]. Similar discordances between hormone receptor content of primary breast cancer versus metastasis have also been recently documented in several other studies [16,17] and loss of ER was associated with a significantly shorter median survival.…”

“…Basal-like cancers have a poor prognosis and are not amenable to treatment with either endocrine therapy or trastuzumab because they are hormone receptor-negative and do not show HER2 overexpression or amplification. It has recently been reported the implication of BRCA-1 loss of function in this subtype of breast cancer [8]. Our patient was tested for BRCA 1 and BRCA-2 genes and they didn't show any significant mutation pattern.…”

p16 loss rescues functional decline of Brca1-deficient mammary stem cells

“…19,20 To directly determine the role of loss of function of Brca1 in controlling MECs, we used Brca1 f/¡ ;MMTVCre (Brca1 f/¡ ;MC) mice, in which MMTV-cre is active in virgin epithelia and mammary glands from these mice express <5% of Brca1 protein and mRNA relative to the levels in Brca1 f/C ;MC mice, as we described previously. 19,27 We compared p16 expression in Brca1 (Fig.…”

“…20,27 Primary antibodies used are as follows: p16 (Santa Cruz Biotechnology), Ki67 (Novocastra Laboratories, Newcastle upon Tyne, UK), gH2AX (Cell Signaling). The IACUC (Institutional Animal Care and Use Committee) at the University of Miami approved all procedures.…”

“…[16][17][18] We have recently discovered that heterozygous germline deletion or specific depletion of Brca1 in mouse epithelium induce senescence in MECs. 19,20 Whether Brca1 loss affects mammary stem cell function is poorly understood.…”