Rats; Humans; Animals; Rats, Inbred ACI; Rats, Sprague-Dawley; Neoplasms; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Multidisciplinary; Physics and Astronomy (all); General Physics and Astronomy; General Biochemistry, Genetics and Molecular Biology; General Chemistry
Abstract :
[en] 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.
Disciplines :
Oncology
Author, co-author :
Alečković, Maša ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Cristea, Simona; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA ; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
Gil Del Alcazar, Carlos R; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Yan, Pengze; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Ding, Lina; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Krop, Ethan D; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Harper, Nicholas W; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Rojas Jimenez, Ernesto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Lu, Donghao; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
Gulvady, Anushree C; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Foidart, Pierre ; Centre Hospitalier Universitaire de Liège - CHU > > Service d'oncologie médicale ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Seehawer, Marco; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
Diciaccio, Benedetto; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Murphy, Katherine C ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Pyrdol, Jason; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA
Anand, Jayati; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Garza, Kodie; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Wucherpfennig, Kai W ; Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA ; Department of Immunology, Harvard Medical School, Boston, MA, 02115, USA
Tamimi, Rulla M; Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA ; Department of Epidemiology, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA
Michor, Franziska ; Department of Data Science, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. michor@jimmy.harvard.edu ; Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, MA, 02138, USA. michor@jimmy.harvard.edu ; Department of Biostatistics, Harvard T. H. Chan School of Public Health, Boston, MA, 02115, USA. michor@jimmy.harvard.edu ; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA. michor@jimmy.harvard.edu ; The Broad Institute of MIT and Harvard, Cambridge, MA, 02138, USA. michor@jimmy.harvard.edu ; The Ludwig Center at Harvard, Boston, MA, 02115, USA. michor@jimmy.harvard.edu
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. kornelia_polyak@dfci.harvard.edu ; Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu ; Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu ; Center for Cancer Evolution, Dana-Farber Cancer Institute, Boston, MA, USA. kornelia_polyak@dfci.harvard.edu ; The Broad Institute of MIT and Harvard, Cambridge, MA, 02138, USA. kornelia_polyak@dfci.harvard.edu ; The Ludwig Center at Harvard, Boston, MA, 02115, USA. kornelia_polyak@dfci.harvard.edu ; Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. kornelia_polyak@dfci.harvard.edu
NIH - National Institutes of Health NCI - National Cancer Institute
Funding text :
We thank Drs. Jeffrey Wrana (U. Toronto), Kyla Driscoll (Eli Lilly), Jacqueline Doody, Fernando Lopez Casillas (U. Mexico), and Rotraud Wiser (U. Vienna), and members of our laboratories for their critical reading of this manuscript and useful discussions. We thank James Shull (U. Wisconsin) for his advice on ACI rat tumorigenesis studies. We thank Zach Herbert and the staff of the DFCI Molecular Biology Core Facility for their dedication and technical expertise and the DFCI Animal Facility staff for their help with the gavage of rats. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Rodent Histopathology Core, which provided tissue processing and histological service. We particularly thank pathologists Peter M. Howley for providing his expertise. We also thank the Dana-Farber Flow Cytometry Core staff for help with FACS. This work was supported by National Cancer Institute P01 CA080111 (K.P.), R35 CA197623 (K.P.), the Susan G. Komen Foundation (K.P.), the DFCI Center for Cancer Evolution (to F.M. and K.P.), the DFCI Physical Sciences-Oncology Center (U54 CA193461, to F.M. and K.P.), and the DFCI Claudia Adams Barr Program (C.R.G.). S.C. was supported by the Swiss National Science Foundation, project P400PB_183830. The Nurses’ Health Studies were supported by the National Cancer Institute UM1 CA186107, P01 CA87969, R01 CA49449, U01 CA176726, and R01 CA67262. We would also like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for the analyses and interpretation of these data.We thank Drs. Jeffrey Wrana (U. Toronto), Kyla Driscoll (Eli Lilly), Jacqueline Doody, Fernando Lopez Casillas (U. Mexico), and Rotraud Wiser (U. Vienna), and members of our laboratories for their critical reading of this manuscript and useful discussions. We thank James Shull (U. Wisconsin) for his advice on ACI rat tumorigenesis studies. We thank Zach Herbert and the staff of the DFCI Molecular Biology Core Facility for their dedication and technical expertise and the DFCI Animal Facility staff for their help with the gavage of rats. We thank Dana-Farber/Harvard Cancer Center in Boston, MA, for the use of the Rodent Histopathology Core, which provided tissue processing and histological service. We particularly thank pathologists Peter M. Howley for providing his expertise. We also thank the Dana-Farber Flow Cytometry Core staff for help with FACS. This work was supported by National Cancer Institute P01 CA080111 (K.P.), R35 CA197623 (K.P.), the Susan G. Komen Foundation (K.P.), the DFCI Center for Cancer Evolution (to F.M. and K.P.), the DFCI Physical Sciences-Oncology Center (U54 CA193461, to F.M. and K.P.), and the DFCI Claudia Adams Barr Program (C.R.G.). S.C. was supported by the Swiss National Science Foundation, project P400PB_183830. The Nurses’ Health Studies were supported by the National Cancer Institute UM1 CA186107, P01 CA87969, R01 CA49449, U01 CA176726, and R01 CA67262. We would also like to thank the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for the analyses and interpretation of these data.
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