Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ

Lina Ding; Ying Su; Anne Fassl; Kunihiko Hinohara; Xintao Qiu; Nicholas W Harper; Sung Jin Huh; Noga Bloushtain-Qimron; Bojana Jovanović; Muhammad Ekram; Xiaoyuan Zi; William C Hines; Maša Alečković; Carlos Gil Del Alcazar; Ryan J Caulfield; Dennis M Bonal; Quang-De Nguyen; Vanessa F Merino; Sibgat Choudhury; Gabrielle Ethington; Laura Panos; Michael Grant; William Herlihy; Alfred Au; Gedge D Rosson; Pedram Argani; Andrea L Richardson; Deborah Dillon; D Craig Allred; Kirsten Babski; Elizabeth Min Hui Kim; Charles H McDonnell 3rd; Jon Wagner; Ron Rowberry; Kristie Bobolis; Celina G Kleer; E Shelley Hwang; Joanne L Blum; Simona Cristea; Piotr Sicinski; Rong Fan; Henry W Long; Saraswati Sukumar; So Yeon Park; Judy E Garber; Mina Bissell; Jun Yao; Kornelia Polyak

doi:10.1038/s41467-019-12125-5

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ

Nat Commun. 2019 Sep 13;10(1):4182. doi: 10.1038/s41467-019-12125-5.

Authors

Lina Ding^{1

2

3}, Ying Su^{1

2

3

4}, Anne Fassl^{5

6}, Kunihiko Hinohara^{1

2

3

7}, Xintao Qiu⁸, Nicholas W Harper¹, Sung Jin Huh^{1

2

3

9}, Noga Bloushtain-Qimron^{1

10}, Bojana Jovanović^{1

2

3}, Muhammad Ekram^{1

2

3

11}, Xiaoyuan Zi^{12

13}, William C Hines^{14

15}, Maša Alečković^{1

2

3}, Carlos Gil Del Alcazar^{1

2

3}, Ryan J Caulfield¹⁶, Dennis M Bonal¹⁶, Quang-De Nguyen¹⁶, Vanessa F Merino¹⁷, Sibgat Choudhury^{1

2

3

18}, Gabrielle Ethington¹⁹, Laura Panos¹⁹, Michael Grant¹⁹, William Herlihy¹⁹, Alfred Au²⁰, Gedge D Rosson¹⁷, Pedram Argani¹⁷, Andrea L Richardson^{21

22

23}, Deborah Dillon^{21

22}, D Craig Allred²⁴, Kirsten Babski²⁵, Elizabeth Min Hui Kim^{25

26}, Charles H McDonnell 3rd²⁵, Jon Wagner²⁵, Ron Rowberry²⁵, Kristie Bobolis²⁵, Celina G Kleer²⁷, E Shelley Hwang^{20

28}, Joanne L Blum¹⁹, Simona Cristea^{29

30

31}, Piotr Sicinski^{5

6}, Rong Fan¹², Henry W Long^{1

8}, Saraswati Sukumar¹⁷, So Yeon Park³², Judy E Garber^{1

2

3}, Mina Bissell¹⁴, Jun Yao³³, Kornelia Polyak^{34

35

36

37

38}

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, 02215, USA.
² Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA.
³ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
⁴ Deciphera Pharmaceuticals, Waltham, MA, USA.
⁵ Department of Cancer Biology, Dana-Farber Cancer Institute Boston, Boston, MA, 02215, USA.
⁶ Department of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA, 02115, USA.
⁷ Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁸ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA.
⁹ ImmunoGen, Inc, Waltham, MA, USA.
¹⁰ EMEA Site Intelligence and Activation, Tel Aviv, Israel.
¹¹ WuXi NextCODE, Cambridge, MA, USA.
¹² Department of Biomedical Engineering, Yale University, New Haven, CT, 06511, USA.
¹³ Second Military Medical University, Shanghai, 200433, P.R. China.
¹⁴ Lawrence Berkeley National Laboratory, Berkeley, CA, 94720, USA.
¹⁵ University of New Mexico School of Medicine, Albuquerque, NM, USA.
¹⁶ Lurie Family Imaging Center, Center for Biomedical Imaging in Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, 02215, USA.
¹⁷ Johns Hopkins University School of Medicine, Baltimore, MD, 21231, USA.
¹⁸ Metamark Genetics Inc, Worcester, MA, USA.
¹⁹ Baylor-Charles A. Sammons Cancer Center, Dallas, TX, 75246, USA.
²⁰ University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94143, USA.
²¹ Department of Pathology, Brigham and Women's Hospital, Boston, MA, 02115, USA.
²² Department of Pathology, Harvard Medical School, Boston, MA, 02115, USA.
²³ Johns Hopkins Medical Institutions, Baltimore, MD, USA.
²⁴ Department of Pathology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
²⁵ Sutter Roseville Medical Center, Roseville, CA, 95661, USA.
²⁶ Cancer Treatment Centers of America, Atlanta, GA, USA.
²⁷ Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA.
²⁸ Duke University, Durham, NC, USA.
²⁹ Department of Data Science, Dana-Farber Cancer Institute Boston, Boston, MA, 02215, USA.
³⁰ Department of Biostatistics, Harvard T. H. Chan School of Public Health Boston, Boston, MA, 02215, USA.
³¹ Department of Stem Cell and Regenerative Biology, Harvard University Cambridge, Cambridge, MA, 02138, USA.
³² Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
³³ MD Anderson Cancer Center, Houston, TX, 77030, USA.
³⁴ Department of Medical Oncology, Dana-Farber Cancer Institute Boston, Boston, MA, 02215, USA. [email protected].
³⁵ Department of Medicine, Brigham and Women's Hospital, Boston, MA, 02115, USA. [email protected].
³⁶ Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA. [email protected].
³⁷ Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA. [email protected].
³⁸ Harvard Stem Cell Institute, Cambridge, MA, 02138, USA. [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
BRCA1 Protein / genetics
BRCA1 Protein / metabolism*
BRCA2 Protein / genetics
BRCA2 Protein / metabolism*
Carcinoma, Ductal, Breast / genetics
Carcinoma, Ductal, Breast / metabolism*
Cell Line, Tumor
Cell Proliferation / genetics
Cell Proliferation / physiology
Female
Fluorescent Antibody Technique
Germ-Line Mutation / genetics
Humans
Immunohistochemistry
Mice
Mutation / genetics*
T Cell Transcription Factor 1 / genetics
T Cell Transcription Factor 1 / metabolism
Transcription Factors / genetics
Transcription Factors / metabolism
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism

Substances

BRCA1 Protein
BRCA2 Protein
T Cell Transcription Factor 1
TCF7 protein, human
TP63 protein, human
Transcription Factors
Tumor Suppressor Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding