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 EthingtonLaura 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, 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number4182
JournalNature communications
Volume10
Issue number1
DOIs
StatePublished - Dec 1 2019

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Carcinoma, Intraductal, Noninfiltrating
mutations
breast
Cell Differentiation
cancer
Tissue
Breast
Mutation
Chromatin
cells
Germ-Line Mutation
chromatin
progressions
Tumors
Breast Neoplasms
Transcription Factors
mammary glands
Genes
Mutation Rate
perturbation

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ. / 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; Gil del Alcazar, Carlos; 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; Yeon Park, So; Garber, Judy E.; Bissell, Mina; Yao, Jun; Polyak, Kornelia.

In: Nature communications, Vol. 10, No. 1, 4182, 01.12.2019.

Research output: Contribution to journalArticle

Ding, L, Su, Y, Fassl, A, Hinohara, K, Qiu, X, Harper, NW, Huh, SJ, Bloushtain-Qimron, N, Jovanović, B, Ekram, M, Zi, X, Hines, WC, Alečković, M, Gil del Alcazar, C, Caulfield, RJ, Bonal, DM, Nguyen, QD, Merino, VF, Choudhury, S, Ethington, G, Panos, L, Grant, M, Herlihy, W, Au, A, Rosson, GD, Argani, P, Richardson, AL, Dillon, D, Allred, DC, Babski, K, Kim, EMH, McDonnell, CH, Wagner, J, Rowberry, R, Bobolis, K, Kleer, CG, Hwang, ES, Blum, JL, Cristea, S, Sicinski, P, Fan, R, Long, HW, Sukumar, S, Yeon Park, S, Garber, JE, Bissell, M, Yao, J & Polyak, K 2019, 'Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ', Nature communications, vol. 10, no. 1, 4182. https://doi.org/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 ; Gil del Alcazar, Carlos ; 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 ; Yeon Park, So ; Garber, Judy E. ; Bissell, Mina ; Yao, Jun ; Polyak, Kornelia. / Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ. In: Nature communications. 2019 ; Vol. 10, No. 1.
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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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AU - Su, Ying

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AU - Hinohara, Kunihiko

AU - Qiu, Xintao

AU - Harper, Nicholas W.

AU - Huh, Sung Jin

AU - Bloushtain-Qimron, Noga

AU - Jovanović, Bojana

AU - Ekram, Muhammad

AU - Zi, Xiaoyuan

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AU - Gil del Alcazar, Carlos

AU - Caulfield, Ryan J.

AU - Bonal, Dennis M.

AU - Nguyen, Quang De

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AU - Choudhury, Sibgat

AU - Ethington, Gabrielle

AU - Panos, Laura

AU - Grant, Michael

AU - Herlihy, William

AU - Au, Alfred

AU - Rosson, Gedge D.

AU - Argani, Pedram

AU - Richardson, Andrea L.

AU - Dillon, Deborah

AU - Allred, D. Craig

AU - Babski, Kirsten

AU - Kim, Elizabeth Min Hui

AU - McDonnell, Charles H.

AU - Wagner, Jon

AU - Rowberry, Ron

AU - Bobolis, Kristie

AU - Kleer, Celina G.

AU - Hwang, E. Shelley

AU - Blum, Joanne L.

AU - Cristea, Simona

AU - Sicinski, Piotr

AU - Fan, Rong

AU - Long, Henry W.

AU - Sukumar, Saraswati

AU - Yeon Park, So

AU - Garber, Judy E.

AU - Bissell, Mina

AU - Yao, Jun

AU - Polyak, Kornelia

PY - 2019/12/1

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N2 - 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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