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

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.

Authors:
 [1];  [2];  [3];  [4];  [5];  [5];  [6];  [7];  [8];  [9]; ORCiD logo [10];  [11]; ORCiD logo [8];  [5]; ORCiD logo [5];  [5];  [12];  [13];  [14];  [14] more »;  [14];  [14];  [15];  [12];  [12];  [16];  [17];  [18];  [19];  [20];  [19];  [19];  [19];  [19];  [21];  [22];  [14];  [23]; ORCiD logo [3]; ORCiD logo [24]; ORCiD logo [5];  [12];  [25];  [26]; ORCiD logo [27];  [28]; ORCiD logo [29];  [8] « less
  1. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  2. Deciphera Pharmaceuticals, Waltham, MA (United States); Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  3. Harvard Medical School, Boston, MA (United States)
  4. Nagoya Univ. Graduate School of Medicine (Japan); Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  5. Dana-Farber Cancer Inst., Boston, MA (United States)
  6. ImmunoGen, Inc., Waltham, MA (United States); Harvard Medical School, Boston, MA (United States)
  7. EMEA Site Intelligence and Activation, Tel Aviv (Israel); Dana-Farber Cancer Inst., Boston, MA (United States)
  8. Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  9. WuXi NextCODE, Cambridge, MA (United States); Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  10. Second Military Medical Univ., Shanghai (China); Yale Univ., New Haven, CT (United States)
  11. Univ. of New Mexico School of Medicine, Albuquerque, NM (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  12. Johns Hopkins Univ., Baltimore, MD (United States). School of Medicine
  13. Metamark Genetics, Inc., Worcester, MA (United States); Harvard Medical School, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  14. Baylor-Charles A. Sammons Cancer Center, Dallas, TX (United States)
  15. Univ. of California San Francisco Helen Diller Family Comprehensive Cancer Center, CA (United States)
  16. Johns Hopkins Medical Institutions, Baltimore, MD (United States); Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  17. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  18. Washington Univ. School of Medicine, St. Louis, MO (United States)
  19. Sutter Roseville Medical Center, Roseville, CA (United States)
  20. Cancer Treatment Centers of America, Atlanta, GA (United States); Sutter Roseville Medical Center, Roseville, CA (United States)
  21. Univ. of Michigan, Ann Arbor, MI (United States)
  22. Duke Univ., Durham, NC (United States); Univ. of California San Francisco Helen Diller Family Comprehensive Cancer Center, CA (United States)
  23. Harvard Univ., Cambridge, MA (United States); Harvard T. H. Chan School of Public Health, Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  24. Yale Univ., New Haven, CT (United States)
  25. Seoul National Univ. College of Medicine (Korea, Republic of)
  26. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States)
  27. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  28. MD Anderson Cancer Center, Houston, TX (United States)
  29. Harvard Stem Cell Inst., Cambridge, MA (United States); Dana-Farber Cancer Inst., Boston, MA (United States); Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1572055
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature Communications
Additional Journal Information:
Journal Volume: 10; Journal Issue: 1; Journal ID: ISSN 2041-1723
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Ding, Lina, Su, Ying, Fassl, Anne, Hinohara, Kunihiko, Qiu, Xintao, Harper, Nicholas W., Huh, Sung Jin, Bloushtain-Qimron, Noga, Jovanović, Bojana, Ekram, Muhammad, Zi, Xiaoyuan, Hines, William C., Alečković, Maša, Caulfield, Ryan J., Bonal, Dennis M., Nguyen, Quang-De, Merino, Vanessa F., Choudhury, Sibgat, Ethington, Gabrielle, Panos, Laura, Grant, Michael, Herlihy, William, Au, Alfred, Rosson, Gedge D., Argani, Pedram, Richardson, Andrea L., Dillon, Deborah, Allred, D. Craig, Babski, Kirsten, Kim, Elizabeth Min Hui, McDonnell, Charles H., Wagner, Jon, Rowberry, Ron, Bobolis, Kristie, Kleer, Celina G., Hwang, E. Shelley, Blum, Joanne L., Cristea, Simona, Sicinski, Piotr, Fan, Rong, Long, Henry W., Sukumar, Saraswati, Park, So Yeon, Garber, Judy E., Bissell, Mina, Yao, Jun, Polyak, Kornelia, and del Alcazar, Carlos Gil. Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ. United States: N. p., 2019. Web. doi:10.1038/s41467-019-12125-5.
Ding, Lina, Su, Ying, Fassl, Anne, Hinohara, Kunihiko, Qiu, Xintao, Harper, Nicholas W., Huh, Sung Jin, Bloushtain-Qimron, Noga, Jovanović, Bojana, Ekram, Muhammad, Zi, Xiaoyuan, Hines, William C., Alečković, Maša, Caulfield, Ryan J., Bonal, Dennis M., Nguyen, Quang-De, Merino, Vanessa F., Choudhury, Sibgat, Ethington, Gabrielle, Panos, Laura, Grant, Michael, Herlihy, William, Au, Alfred, Rosson, Gedge D., Argani, Pedram, Richardson, Andrea L., Dillon, Deborah, Allred, D. Craig, Babski, Kirsten, Kim, Elizabeth Min Hui, McDonnell, Charles H., Wagner, Jon, Rowberry, Ron, Bobolis, Kristie, Kleer, Celina G., Hwang, E. Shelley, Blum, Joanne L., Cristea, Simona, Sicinski, Piotr, Fan, Rong, Long, Henry W., Sukumar, Saraswati, Park, So Yeon, Garber, Judy E., Bissell, Mina, Yao, Jun, Polyak, Kornelia, & del Alcazar, Carlos Gil. Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ. United States. doi:10.1038/s41467-019-12125-5.
Ding, Lina, Su, Ying, Fassl, Anne, Hinohara, Kunihiko, Qiu, Xintao, Harper, Nicholas W., Huh, Sung Jin, Bloushtain-Qimron, Noga, Jovanović, Bojana, Ekram, Muhammad, Zi, Xiaoyuan, Hines, William C., Alečković, Maša, Caulfield, Ryan J., Bonal, Dennis M., Nguyen, Quang-De, Merino, Vanessa F., Choudhury, Sibgat, Ethington, Gabrielle, Panos, Laura, Grant, Michael, Herlihy, William, Au, Alfred, Rosson, Gedge D., Argani, Pedram, Richardson, Andrea L., Dillon, Deborah, Allred, D. Craig, Babski, Kirsten, Kim, Elizabeth Min Hui, McDonnell, Charles H., Wagner, Jon, Rowberry, Ron, Bobolis, Kristie, Kleer, Celina G., Hwang, E. Shelley, Blum, Joanne L., Cristea, Simona, Sicinski, Piotr, Fan, Rong, Long, Henry W., Sukumar, Saraswati, Park, So Yeon, Garber, Judy E., Bissell, Mina, Yao, Jun, Polyak, Kornelia, and del Alcazar, Carlos Gil. Fri . "Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ". United States. doi:10.1038/s41467-019-12125-5. https://www.osti.gov/servlets/purl/1572055.
@article{osti_1572055,
title = {Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ},
author = {Ding, Lina and Su, Ying and Fassl, Anne and Hinohara, Kunihiko and Qiu, Xintao and Harper, Nicholas W. and Huh, Sung Jin and Bloushtain-Qimron, Noga and Jovanović, Bojana and Ekram, Muhammad and Zi, Xiaoyuan and Hines, William C. and Alečković, Maša and Caulfield, Ryan J. and Bonal, Dennis M. and Nguyen, Quang-De and Merino, Vanessa F. and Choudhury, Sibgat and Ethington, Gabrielle and Panos, Laura and Grant, Michael and Herlihy, William and Au, Alfred and Rosson, Gedge D. and Argani, Pedram and Richardson, Andrea L. and Dillon, Deborah and Allred, D. Craig and Babski, Kirsten and Kim, Elizabeth Min Hui and McDonnell, Charles H. and Wagner, Jon and Rowberry, Ron and Bobolis, Kristie and Kleer, Celina G. and Hwang, E. Shelley and Blum, Joanne L. and Cristea, Simona and Sicinski, Piotr and Fan, Rong and Long, Henry W. and Sukumar, Saraswati and Park, So Yeon and Garber, Judy E. and Bissell, Mina and Yao, Jun and Polyak, Kornelia and del Alcazar, Carlos Gil},
abstractNote = {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.},
doi = {10.1038/s41467-019-12125-5},
journal = {Nature Communications},
number = 1,
volume = 10,
place = {United States},
year = {2019},
month = {9}
}

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