Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations

During aging in the human mammary gland, luminal epithelial cells lose lineage fidelity by expressing markers normally expressed in myoepithelial cells. We hypothesize that loss of lineage fidelity is a general manifestation of epithelia that are susceptible to cancer initiation. In the present study, we show that histologically normal breast tissue from younger women who are susceptible to breast cancer, as a result of harboring a germline mutation in BRCA1, BRCA2 or PALB2 genes, exhibits hallmarks of accelerated aging. These include proportionately increased luminal epithelial cells that acquired myoepithelial markers, decreased proportions of myoepithelial cells and a basal differentiation bias or failure of differentiation of cKit+ pro- genitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflam- matory- and cancer-related pathways. We have identified breast-aging hallmarks that reflect a convergent biology of cancer susceptibility, regardless of the specific underlying genetic or age-dependent risk or the associated breast cancer subtype.We thank C. Thai, A. Sanchez, T. Chevez, A. Nunez and M. V. Robles for their help with tissue collection and clinical information from the women participating in our study. We also thank M. Miyano for assistance with immunofluorescence images, M. Basam for help with coding, and our patient advocates S. Samson and S. Preto for providing much needed context. Funding was provided by: DOD CDMRP (BC141351 Era of Hope Scholar Award and BC181737), Hilton-Ludwig Foundation and City of Hope Center for Cancer and Aging to M.A.L.; National Institutes of Health/National Cancer Institute (NIH/NCI) grants (nos. R01CA237602, U01CA244109, R33AG059206 and R01EB024989 to M.A.L. and nos. R01CA170851, P20CA24619, R01CA192914 and U01CA189283 to V.E.S.) and NCI Cancer Metabolism Training Program Postdoctoral Fellowship T32CA221709 to R.W.S. Research reported in this publication included work performed in the Integrative Genomics and Bioinformatics, Analytical Cytometry, and Biomarker Analysis and Validation Cores supported by the NCI of the NIH under grant no. P30CA033572. M.R.S. and J.C.G. are supported by US Department of Energy under contract no. DE-AC02-05CH11231. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript