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.

Details

Title
Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ
Author
Ding, Lina 1 ; Su, Ying 2 ; Fassl, Anne 3 ; Hinohara, Kunihiko 4 ; Qiu, Xintao 5 ; Harper, Nicholas W 6 ; Sung Jin Huh 7 ; Noga Bloushtain-Qimron 8 ; Jovanović, Bojana 1 ; Muhammad Ekram 9 ; Zi, Xiaoyuan 10   VIAFID ORCID Logo  ; Hines, William C 11 ; Alečković, Maša 1   VIAFID ORCID Logo  ; Gil del Alcazar, Carlos 1 ; Caulfield, Ryan J 12 ; Bonal, Dennis M 12   VIAFID ORCID Logo  ; Quang-De Nguyen 12 ; Merino, Vanessa F 13 ; Choudhury, Sibgat 14 ; Ethington, Gabrielle 15 ; Panos, Laura 15 ; Grant, Michael 15 ; Herlihy, William 15 ; Au, Alfred 16 ; Rosson, Gedge D 13 ; Argani, Pedram 13 ; Richardson, Andrea L 17 ; Dillon, Deborah 18 ; Allred, D Craig 19 ; Babski, Kirsten 20 ; Hui Kim, Elizabeth Min 21 ; McDonnell, Charles H, III 20 ; Wagner, Jon 20 ; Rowberry, Ron 20 ; Bobolis, Kristie 20 ; Kleer, Celina G 22 ; E Shelley Hwang 23 ; Blum, Joanne L 15 ; Cristea, Simona 24 ; Sicinski, Piotr 3   VIAFID ORCID Logo  ; Fan, Rong 25   VIAFID ORCID Logo  ; Long, Henry W 26   VIAFID ORCID Logo  ; Sukumar, Saraswati 13 ; Park, So Yeon 27 ; Garber, Judy E 1 ; Bissell, Mina 28   VIAFID ORCID Logo  ; Yao, Jun 29 ; Polyak, Kornelia 30   VIAFID ORCID Logo 

 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 
 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 
 Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, USA 
 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 
 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA 
 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA 
 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 
 Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, USA; EMEA Site Intelligence and Activation, Tel Aviv, Israel 
 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 
Pages
1-16
Publication year
2019
Publication date
Sep 2019
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
ProQuest document ID
2290064700
Copyright
© 2019. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.