Perturbed myoepithelial cell differentiation in BRCA mutation carriers and in ductal carcinoma in situ.
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.
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, Q-D; 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; Park, SY; Garber, JE; Bissell, M; Yao, J; Polyak, K
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