aging; breast cancer risk; breast tumorigenesis; mammary tumors; midkine; single-cell profiling; Midkine; MDK protein, human; Methylnitrosourea; Animals; Female; Humans; Rats; Carcinogenesis/genetics; Mammary Glands, Animal/pathology; Mammary Glands, Animal/metabolism; Cell Proliferation; Mammary Neoplasms, Experimental/pathology; Mammary Neoplasms, Experimental/genetics; Mammary Neoplasms, Experimental/chemically induced; Mammary Neoplasms, Experimental/metabolism; Cell Transformation, Neoplastic/genetics; Cell Transformation, Neoplastic/metabolism; Cell Transformation, Neoplastic/pathology; Signal Transduction; Methylnitrosourea/toxicity; Midkine/metabolism; Midkine/genetics; Breast Neoplasms/pathology; Breast Neoplasms/metabolism; Breast Neoplasms/etiology; Breast Neoplasms/genetics; Aging/pathology; Breast Neoplasms; Carcinogenesis; Cell Transformation, Neoplastic; Mammary Glands, Animal; Mammary Neoplasms, Experimental; Oncology; Cancer Research
Abstract :
[en] Aging is a pivotal risk factor for cancer, yet the underlying mechanisms remain poorly defined. Here, we explore age-related changes in the rat mammary gland by single-cell multiomics. Our findings include increased epithelial proliferation, loss of luminal identity, and decreased naive B and T cells with age. We discover a luminal progenitor population unique to old rats with profiles reflecting precancerous changes and identify midkine (Mdk) as a gene upregulated with age and a regulator of age-related luminal progenitors. Midkine treatment of young rats mimics age-related changes via activating PI3K-AKT-SREBF1 pathway and promotes nitroso-N-methylurea-induced mammary tumorigenesis. Midkine levels increase with age in human blood and mammary epithelium, and higher MDK in normal breast tissue is associated with higher breast cancer risk in younger women. Our findings reveal a link between aging and susceptibility to tumor initiation and identify midkine as a mediator of age-dependent increase in breast tumorigenesis.
Disciplines :
Oncology
Author, co-author :
Yan, Pengze; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Jimenez, Ernesto Rojas; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Li, Zheqi; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Bui, Triet; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Seehawer, Marco; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Nishida, Jun; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Foidart, Pierre ; Université de Liège - ULiège > Département des sciences cliniques ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Stevens, Laura E; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA
Xie, Yingtian; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Gomez, Miguel Munoz; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Park, So Yeon; Department of Pathology, Seoul National University, Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea
Long, Henry W; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA
Polyak, Kornelia ; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Medicine, Harvard Medical School, Boston, MA 02115, USA, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA, Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA 02215, USA, Department of Pathology, Seoul National University, Bundang Hospital, Seoul National University College of Medicine, Seongnam, Republic of Korea, Harvard Stem Cell Institute, Cambridge, MA 02142, USA. Electronic address: kornelia_polyak@dfci.harvard.edu
SWCRF - Samuel Waxman Cancer Research Foundation Susan G. Komen Breast Cancer Foundation Mark Foundation for Cancer Research ACS - American Cancer Society NCI - National Cancer Institute
Funding text :
We thank members of our laboratories for critical reading of the manuscript and discussions. We thank the Dana-Farber Cancer Institute Molecular Biology, Molecular Imaging Core, Flow Cytometry Core Facilities, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core facility, Dana-Farber Cancer Institute Animal Resource Facilities, and Translational Immunogenomics Laboratory for outstanding services. We thank the National Institute of Aging for providing aged rats. This research was supported by the National Cancer Institute R35 CA197623 (K.P.) and P01 CA250959 (K.P. and H.L.), the Susan G. Komen Foundation (K.P.), and a joint grant by the Samuel Waxman Cancer Research Foundation and The Mark Foundation For Cancer Research (K.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health/NCI.We thank members of our laboratories for critical reading of the manuscript and discussions. We thank the Dana-Farber Cancer Institute Molecular Biology, Molecular Imaging Core, Flow Cytometry Core Facilities, Dana-Farber/Harvard Cancer Center Rodent Histopathology Core facility, Dana-Farber Cancer Institute Animal Resource Facilities, Translational Immunogenomics Laboratory and Neurobiology Imaging Facility, HMS for outstanding services. We thank the National Institute of Aging for providing aged rats. This research was supported by the National Cancer Institute R35 CA197623 (K.P.) and P01 CA250959 (K.P. and H.L.), the Susan G. Komen Foundation (K.P.), and a joint grant by the Samuel Waxman Cancer Research Foundation and The Mark Foundation For Cancer Research (K.P.). K.P.. is an American Cancer Society Research Professor. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health / NCI .
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