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

Shalabi, Sundus F.; Miyano, Masaru; Sayaman, Rosalyn W.; Lopez, Jennifer C.; Jokela, Tiina A.; Todhunter, Michael E.; Hinz, Stefan; Garbe, James C.; Stampfer, Martha R.; Kessenbrock, Kai; Seewaldt, Victoria E.; LaBarge, Mark A.

doi:10.1038/s43587-021-00104-9

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

Journal Article · Tue Sep 14 00:00:00 EDT 2021 · Nature Aging

DOI:https://doi.org/10.1038/s43587-021-00104-9· OSTI ID:2469719

^[1]; Miyano, Masaru ^[2]; Sayaman, Rosalyn W. ^[3]; Lopez, Jennifer C. ^[2]; Jokela, Tiina A. ^[2]; Todhunter, Michael E. ^[2]; Hinz, Stefan ^[2]; ^[4]; Stampfer, Martha R. ^[4]; ^[5]; ^[2]; ^[6]

City of Hope, Duarte, CA (United States); Al-Quds University, Jerusalem (Palestine)
City of Hope, Duarte, CA (United States)
City of Hope, Duarte, CA (United States); Univ. of California, San Francisco, CA (United States); Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Univ. of California, Irvine, CA (United States)
City of Hope, Duarte, CA (United States); Univ. of Bergen (Norway)

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⁺ progenitors. High-risk luminal and myoepithelial cells are transcriptionally enriched for genes of the opposite lineage, inflammatory- 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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2469719

Journal Information:: Nature Aging, Journal Name: Nature Aging Journal Issue: 9 Vol. 1; ISSN 2662-8465

Publisher:: Springer NatureCopyright Statement

Country of Publication:: United States

Language:: English

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