Preneoplastic stromal cells promote BRCA1-mediated breast tumorigenesis.

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Publication Year:
2023
Authors:
Kevin Nee, Dennis Ma, Quy H Nguyen, Maren Pein, Nicholas Pervolarakis, Jacob Insua-Rodriguez, Yanwen Gong, Grace Hernandez, Hamad Alshetaiwi, Justice Williams, Maha Rauf, Kushal Rajiv Dave, Keerti Boyapati, Aliza Hasnain, Christian Calderon, Anush Markaryan, Robert Edwards, Erin Lin, Ritesh Parajuli, Peijie Zhou, Qing Nie, Sundus Shalabi, Mark A LaBarge, Kai Kessenbrock
PubMed ID:
36914836
Funding Grants:
Public Summary:
Women with germline BRCA1 mutations (BRCA1+/mut) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1+/mut is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1+/mut and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1+/mut stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1+/mut may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.
Scientific Abstract:
Women with germline BRCA1 mutations (BRCA1(+/mut)) have increased risk for hereditary breast cancer. Cancer initiation in BRCA1(+/mut) is associated with premalignant changes in breast epithelium; however, the role of the epithelium-associated stromal niche during BRCA1-driven tumor initiation remains unclear. Here we show that the premalignant stromal niche promotes epithelial proliferation and mutant BRCA1-driven tumorigenesis in trans. Using single-cell RNA sequencing analysis of human preneoplastic BRCA1(+/mut) and noncarrier breast tissues, we show distinct changes in epithelial homeostasis including increased proliferation and expansion of basal-luminal intermediate progenitor cells. Additionally, BRCA1(+/mut) stromal cells show increased expression of pro-proliferative paracrine signals. In particular, we identify pre-cancer-associated fibroblasts (pre-CAFs) that produce protumorigenic factors including matrix metalloproteinase 3 (MMP3), which promotes BRCA1-driven tumorigenesis in vivo. Together, our findings demonstrate that precancerous stroma in BRCA1(+/mut) may elevate breast cancer risk through the promotion of epithelial proliferation and an accumulation of luminal progenitor cells with altered differentiation.