Cells from the breasts of women with mutations that increase their risk of breast cancer show signs of accelerated aging, according to new research . Accelerated aging may make these cells worse at suppressing cancer development, offering both an explanation for the effect of these mutations and an unexplored path for possible treatments.
Most cases of breast cancer don’t have a clear cause, but a small percentage are due to mutations in one of a handful of genes. Many people are aware that women with a mutant form of BRCA1, BRCA2, PALB2, or several other genes have a significantly higher risk of developing breast cancer, but it’s perhaps less commonly known that these women also tend to be diagnosed at younger ages. Together with the fact that many of the mutated genes are involved in repairing DNA damage, this hints at the possibility that aging biology may somehow be involved in the increased cancer risk.
An international team of researchers decided to look deeper into this possibility. They collected breast tissue from women with and without high-risk mutations who had had preventative mastectomies or breast reduction surgery. They examined the identity, gene expression, and functional features of the cells in high-risk and average-risk women of different ages in order to determine whether the high-risk group showed signs of greater biological age, which would explain why they are diagnosed with cancer at younger ages
Prematurely aged cells
With age, the distribution of cells of different identities in breast tissue shifts; luminal epithelial cells increase their share, while myothelial epithelial cells become less common. At the same time, the luminal cells gain some characteristics of myoepithelia in a process the researchers call “loss of lineage fidelity”.
The team found that tissue from high-risk women had a greater proportion of luminal epithelial cells than age-matched average-risk women, and these cells also expressed markers normally seen in myoepithelial cells – in other words, there was a loss of lineage fidelity. The samples from high-risk women looked similar to tissue from older average-risk women. In fact, one of the striking observations in this paper is that these changes in cell identity correlated with age in average-risk women but were independent of age in the high-risk group.
The gene expression profiles told a similar story. About 330 genes were expressed at different levels in age-matched high-risk and average-risk tissue. Again, the difference was similar to the consequences of aging. When compared with samples from average-risk young women, tissue from high-risk young women showed changes in many of the same genes as tissue from average-risk older women.
In other words, a common set of genes is affected by aging or by mutations that increase the risk of breast cancer. Further investigation showed that this set of genes is enriched from inflammatory and cancer-promoting pathways – as the researchers wrote in the paper, it “overlapped with senescence and aging signature genes.”
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.
There are details about more differences between the high-risk and average-risk tissue in the paper, but the overall message is clear. In terms of cell identity changes, gene expression, and some functional tests, the high-risk tissue is biologically older than the average-risk tissue.
It would be interesting to see whether various aging clocks would report the same thing. It’s an intriguing and important finding because it demonstrates a similarity between these various mutations and also explains how they increase the risk of breast cancer, particularly at younger ages.
The convergence of cancer susceptibility and aging biology in this case is striking. Understanding these mutations in terms of aging biology opens the door for longevity research to create potential cancer prevention strategies for carriers of these mutations.
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 Shalabi, SF. Evidence for accelerated aging in mammary epithelia of women carrying germline BRCA1 or BRCA2 mutations. Nature Aging (2021), doi: 10.1038/s43587-021-00104-9
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