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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.

SUBMITTER: Ding L

PROVIDER: S-EPMC6744561 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Ding Lina L Su Ying Y Fassl Anne A Hinohara Kunihiko K Qiu Xintao X Harper Nicholas W NW Huh Sung Jin SJ Bloushtain-Qimron Noga N Jovanović Bojana B Ekram Muhammad M Zi Xiaoyuan X Hines William C WC Alečković Maša M Gil Del Alcazar Carlos C Caulfield Ryan J RJ Bonal Dennis M DM Nguyen Quang-De QD Merino Vanessa F VF Choudhury Sibgat S Ethington Gabrielle G Panos Laura L Grant Michael M Herlihy William W Au Alfred A Rosson Gedge D GD Argani Pedram P Richardson Andrea L AL Dillon Deborah D Allred D Craig DC Babski Kirsten K Kim Elizabeth Min Hui EMH McDonnell Charles H CH Wagner Jon J Rowberry Ron R Bobolis Kristie K Kleer Celina G CG Hwang E Shelley ES Blum Joanne L JL Cristea Simona S Sicinski Piotr P Fan Rong R Long Henry W HW Sukumar Saraswati S Park So Yeon SY Garber Judy E JE Bissell Mina M Yao Jun J Polyak Kornelia K

Nature communications 20190913 1

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 ...[more]

PMID: 31519911

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Project description:Recent studies have revealed that BRCA1 and BRCA2 germline mutation-related breast cancers show frequent overexpression of hypoxia inducible factor-1? (HIF-1?), the key regulator of the hypoxia response. However, the question remained whether hypoxia is a late stage bystander or a true carcinogenetic event in patients with hereditary predisposition. We therefore studied HIF-1? overexpression in ductal carcinoma in situ (DCIS), an established precursor of invasive breast cancer.We used immunohistochemistry to examine the expression of the hypoxia markers HIF-1?, CAIX and Glut-1 in DCIS and available invasive carcinoma lesions of 32 BRCA1, 16 BRCA2 and 77 non-BRCA mutation-related cases. HIF-1? expression was detected in 63% of BRCA1 and 62% of BRCA2 as compared to 34% of non-BRCA mutation-related DCIS cases (p?=?0.005). CAIX overexpression was present in 56% of BRCA1 and 44% of BRCA2 as compared to 6% of non-BRCA mutation-related DCIS cases (p?=?0.000). Glut-1 overexpression was observed in 59% of BRCA1, 75% of BRCA2 and 67% of non-BRCA mutation-related DCIS cases (p?=?0.527). Overall, HIF-1?, CAIX and Glut-1 expression in BRCA mutation-related DCIS matched the expression in the accompanying invasive cancers in 60% or more of cases. In non-BRCA mutation-related cases the expression of the hypoxia markers in DCIS matched the expression in the invasive part in 46% or more of the cases.Although BRCA1 and BRCA2 germline mutation-related invasive breast cancers are different in many ways, the hypoxia-related proteins HIF-1?, CAIX and Glut-1 are expressed in both DCIS and invasive lesions of BRCA1 and BRCA2 mutation carriers. This suggests that hypoxia may already play a role in the DCIS stage of BRCA1 and BRCA2 germline mutation related breast carcinogenesis, and may also drive cancer progression. Hypoxia-related proteins are therefore putative targets for therapy and molecular imaging for early detection and monitoring therapy response in BRCA mutation patients.

Dataset Information

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

Publications

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

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