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Abstract
Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
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1 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA
2 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Deciphera Pharmaceuticals, Waltham, MA, USA
3 Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
4 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Nagoya University Graduate School of Medicine, Nagoya, Japan
5 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
6 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA
7 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; ImmunoGen, Inc, Waltham, MA, USA
8 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; EMEA Site Intelligence and Activation, Tel Aviv, Israel
9 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; WuXi NextCODE, Cambridge, MA, USA
10 Department of Biomedical Engineering, Yale University, New Haven, CT, USA; Second Military Medical University, Shanghai, P.R. China
11 Lawrence Berkeley National Laboratory, Berkeley, CA, USA; University of New Mexico School of Medicine, Albuquerque, NM, USA
12 Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA
13 Johns Hopkins University School of Medicine, Baltimore, MD, USA
14 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Metamark Genetics Inc, Worcester, MA, USA
15 Baylor-Charles A. Sammons Cancer Center, Dallas, TX, USA
16 University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA
17 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA; Johns Hopkins Medical Institutions, Baltimore, MD, USA
18 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA; Department of Pathology, Harvard Medical School, Boston, MA, USA
19 Department of Pathology, Washington University School of Medicine, St. Louis, MO, USA
20 Sutter Roseville Medical Center, Roseville, CA, USA
21 Sutter Roseville Medical Center, Roseville, CA, USA; Cancer Treatment Centers of America, Atlanta, GA, USA
22 Department of Pathology, University of Michigan, Ann Arbor, MI, USA
23 University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, USA; Duke University, Durham, NC, USA
24 Department of Data Science, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Biostatistics, Harvard T. H. Chan School of Public Health Boston, Boston, MA, USA; Department of Stem Cell and Regenerative Biology, Harvard University Cambridge, Cambridge, MA, USA
25 Department of Biomedical Engineering, Yale University, New Haven, CT, USA
26 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
27 Department of Pathology, Seoul National University College of Medicine, Seoul, Korea
28 Lawrence Berkeley National Laboratory, Berkeley, CA, USA
29 MD Anderson Cancer Center, Houston, TX, USA
30 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Department of Medicine, Harvard Medical School, Boston, MA, USA; Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Stem Cell Institute, Cambridge, MA, USA