Year: 2022
Type: article
Abstract: Cancer prevention has a profound impact on cancer-associated mortality and morbidity. We previously identified TGFβ signaling as a candidate regulator of mammary epithelial cells associated with breast cancer risk. Here, we show that short-term TGFBR inhibitor (TGFBRi) treatment of peripubertal ACI inbred and Sprague Dawley outbred rats induces lasting changes and prevents estrogen- and carcinogen-induced mammary tumors, respectively. We identify TGFBRi-responsive cell populations by single cell RNA-sequencing, including a unique epithelial subpopulation designated secretory basal cells (SBCs) with progenitor features. We detect SBCs in normal human breast tissues and find them to be associated with breast cancer risk. Interactome analysis identifies SBCs as the most interactive cell population and the main source of insulin-IGF signaling. Accordingly, inhibition of TGFBR and IGF1R decrease proliferation of organoid cultures. Our results reveal a critical role for TGFβ in regulating mammary epithelial cells relevant to breast cancer and serve as a proof-of-principle cancer prevention strategy.
Source: Nature Communications
Authors: Maša Alečković, Simona Cristea, Carlos R. Gil Del Alcazar, Pengze Yan, Lina Ding, Ethan D. Krop, Nicholas W. Harper, Ernesto Rojas Jimenez, Donghao Lu, Anushree C. Gulvady, Pierre Foidart, Marco Seehawer, Benedetto Diciaccio, Katherine C. Murphy, Jason Pyrdol, Jayati Anand, Kodie Garza, Kai W. Wucherpfennig, Rulla M. Tamimi, Franziska Michor, Kornelia Polyak
Language: English
Topic: TGF-β signaling in diseases
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $5,890
Funders: National Science Foundation, U.S. Department of Health and Human Services, Susan G. Komen for the Cure, Eli Lilly and Company, Dana-Farber Cancer Institute, Dana-Farber/Harvard Cancer Center, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institutes of Health, National Cancer Institute
Awards: Evolution and Treatment Response of Brain, Breast, and Hematologic Malignancies, G1062938757, G142349785, G151562090, Targeting of a Major Immune Evasion Pathway in Triple-negative Breast Cancer, G1817671933, G2031764241, G2214254730, G2750880407, G2930298908, G294025628, G3352250835, G340051698, G3602225402, G361298724, Dietary and Hormonal Determinants of Cancer in Women, G3973866091, G4015507826, G4376790518, G459566519, G4627906632, Premonopausal Hormone Levels and Risk of Breast Cancer, Mechanisms of Breast Development and Carcinogenesis, G479225836, Life Course Cancer Epidemiology Cohort in Women, Targeting intratumor heterogeneity in breast cancer, G5999821407, G6200764915, G625908496, Integrative Single Cell Modeling of Clonal Cancer Progression, G7063308019, G7215281656, G784047723, G885693336
OpenAlex ID: W4311572509