Monday, May 12, 2025
5/12/2025
DNA damage-related stemness program during BRCA1 breast cancer initiation - BRCA1 mutation carriers have a very high life-time risk of developing basal-like breast cancer (BLBC), which is a breast cancer subtype that has unfavorable outcomes and limited treatment options. Thus, there is an urgent need to develop novel strategies to prevent or intercept BRCA1 breast cancer initiation, which would benefit from a better understanding of its early stages of development. BRCA1 BLBC may originate from luminal mammary epithelial cells (MECs), particularly, luminal progenitors (LPs). To study BRCA1 mammary tumor initiation from LPs, we developed a novel mouse model that faithfully recapitulates initiation and progression of BLBC from genetically marked BRCA1-deficient luminal MECs. Characterization of this model revealed growing DNA damage and the related luminal to basal and mesenchymal cell fate change during BRCA1 mammary tumorigenesis. Our studies so far from this mouse model as well as human breast cell lines supported that the aberrant basal/mesenchymal gene expression in BRCA1-deficient MECs may be caused by insufficient repair of interstrand crosslink (ICL) DNA damages. Furthermore, single cell analysis of chromatin accessibility (scATACseq) of premalignant MECs revealed the potential acquisition of a fetal mammary stem cell (fMaSC)-like epigenetic state in premalignant LPs with BRCA1-loss, which may be responsible for their increased expansion and luminal-to-basal/mesenchymal cell fate change. Based on these preliminary findings, we hypothesize that accumulation of DNA damages (particularly ICLs) in BRCA1- deficient luminal MECs enables cell fate plasticity by inducing a fMaSC-like developmental program in them; this stemness program is necessary for breast cancer development from luminal cells and can thus become a target for interception of BRCA1 breast cancer initiation. To test this hypothesis, we propose three Specific Aims. In Aim 1, we will study whether BRCA1-deficient luminal MECs acquire a fMaSC-like program via a key fMaSC-related transcription factor, SOX10, by transplantation and organoid culture assays. In Aim 2, we will determine whether inadequate repair of ICL DNA damages induces stemness in BRCA1-deficient luminal MECs in a SOX10-dependent manner and whether developmental pathways such as Wnt and FGF signaling (both control SOX10 expression/activity during neural crest development) play any key role in this process. In Aim 3, we will focus on Wnt signaling, which is required in BRCA1 tumor-initiating cells (TICs) and may constitute a key component of the potential DNA damage-related stemness program; we will determine if Wnt pathway activation is necessary for BRCA1 mammary tumor initiation genetically and if we can intercept formation of BRCA1 TICs and/or progression of BRCA1 precancer to frank malignancy by using a novel narrow-spectrum Wnt inhibitor that blocks binding of the FZD1/2/7 subfamily of Frizzled (FZD) receptors to Wnt ligands. If successful, we expect that this project may lead to novel targets and agents to prevent or intercept breast cancer initiation from BRCA1-deficient luminal MECs, particularly in high-risk individuals.
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