Abstract
Breast cancer developed in familial BRCA1 mutation carriers bears striking similarities to sporadic basal-like breast tumors. The mechanism underlying the function of BRCA1 in suppressing basal-like breast cancer remains unclear. We previously reported that the deletion of p18Ink4c (p18), an inhibitor of G1 cyclin Ds-dependent CDK4 and CDK6, stimulates mammary luminal progenitor cell proliferation and leads to spontaneous luminal tumor development. We report here that germline mutation of Brca1 in p18-deficient mice blocks the increase of luminal progenitor cells, impairs luminal gene expression and promotes malignant transformation of mammary tumors. Instead of the luminal mammary tumors developed in p18 single-mutant mice, mammary tumors developed in the p18;Brca1 mice, similar to breast cancer developed in familial BRCA1 carriers, exhibited extensive basal-like features and lost the remaining wild-type allele of Brca1. These results reveal distinct functions of the RB and BRCA1 pathways in suppressing luminal and basal-like mammary tumors, respectively. These results also suggest a novel mechanism—causing luminal-to-basal transformation—for the development of basal-like breast cancer in familial BRCA1 carriers and establish a unique mouse model for developing therapeutic strategies to target both luminal and basal-like breast cancers.
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Acknowledgements
This project was initiated at the Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill. We thank Dr Yue Xiong for his invaluable support, discussion and critical reading of the manuscript, Dr Beverly Koller for providing Brca1 germline mutant mice and Drs Anthony Capobianco and Xiangxi Xu for discussions. This study was supported in part by a DOD Idea Award (W81XWH-10-1-0302) and startup funds from the University of Miami Miller School of Medicine to XHP.
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Bai, F., Smith, M., Chan, H. et al. Germline mutation of Brca1 alters the fate of mammary luminal cells and causes luminal-to-basal mammary tumor transformation. Oncogene 32, 2715–2725 (2013). https://doi.org/10.1038/onc.2012.293
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DOI: https://doi.org/10.1038/onc.2012.293
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