Role of p53-Deficiency in BRCA1-Associated Basal-Like Breast Cancer Initiation
Abstract
This proposal will address the Breast Cancer Research Program overarching challenges, “Identify determinants of breast cancer initiation, risk, or susceptibility,” “Prevent breast cancer (primary prevention),” and “Identify what drives breast cancer growth; determine how to stop it.” Women with inherited mutations in the BRCA1 gene are at high risk of developing basal-like breast cancer (BLBC). In addition to their BRCA1 mutations, another common genomic abnormality in their BLBCs is mutations in a tumor-suppressing gene called p53. Many of these p53 mutations lead to truncations of the p53 gene, suggesting loss of the p53 gene may play a key role in development of BLBC from their BRCA1-mutant mammary epithelial cells (MECs). The current treatment and preventative strategies for BRCA1-mutant BLBC include therapies based on platinum or PARP inhibitors, as well as risk-reduction approaches based on annual screening with mammography and MRI (magnetic resonance imaging), prophylactic mastectomies, or prophylactic oophorectomy. Due to the nature of these approaches, less invasive and/or more effective strategies based on rationale design are needed. To achieve this, it is crucial to understand early events during BLBC development from BRCA1-deficient MECs. This proposed project is designed to address this urgent clinical need and is based on our preliminary studies to examine how induced loss of BRCA1 and p53 in luminal MECs leads to initiation of BLBC development. We found that induced loss of p53 in luminal MECs alone led to their expansion but without causing a change in their luminal cell identity directly, whereas induced loss of both BRCA1 and p53 in luminal MECs not only increased their expansion but also caused changes in the identity of the mutated luminal cells, as we observed loss of estrogen receptor (ER)-positive luminal cells and emergence of MECs with features of basal cells. These p53/BRCA1-double mutant cells could grow much better in tissue culture dish and exhibited expression of genes normally expressed in basal MECs or in mammary fibroblasts. These data suggest that in luminal MECs, loss of p53 works together with loss of BRCA1, leading to their enhanced proliferation and alteration in their original cell identity toward ER-negative MEC types. In BRCA1 mutation carriers, every cell carries a defective BRCA1 gene but not every MEC gives rise to BLBC; thus, initiation of BLBC requires acquisition of additional mutations so that their MECs carrying such secondary mutation(s) may obtain a growth advantage and outcompete their neighbors, leading to initiation of BLBC. We hypothesize that loss of p53 is such a cooperating mutational event; we further hypothesize that loss of p53 also plays another important role in facilitating transition of BRCA1-mutant luminal MECs toward an ER-negative, basal-like cell phenotype (i.e., another important feature of BLBC initiation), as a result of deregulated (due to p53 loss) accessibilities of certain luminal and basal genes for their gene expression. To test this hypothesis, we propose two specific aims. In one set of experiments (Aim 1), we will generate mice with loss of one copy of their Brca1 gene (thus mimicking BRCA1 mutation carriers), and then induce loss of p53 in their luminal MECs. We will follow growth of these p53-deficient MECs and determine whether they undergo expansion at the expense of their neighbor cells and whether they also undergo luminal-to-basal cell identity change. Importantly, we will examine whether cyclic changes in levels of female hormones (estrogen, progesterone) during each ovarian cycle play a key role in helping p53/BRCA1-double mutant MECs “win” over their BRCA1-single mutant neighbor MECs; this will be achieved by a set of experiments through modulating hormone levels, including removing ovaries with or without hormone replacement, as well as tamoxifen treatment. As prophylactic oophorectomy and tamoxifen treatment are com
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1810037
Entities
People
- Zhe Li
Organizations
- United States Army