Mark LaBarge, Ph.D., professor in City of Hope’s Department of Population Sciences, and Sundus Shalabi, Ph.D. candidate at the City of Hope speak about Evidence For Accelerated Aging In Mammary Epithelia Of Women Carrying Germline BRCA1 Or BRCA2 Mutations.
Link to Abstract:
https://www.nature.com/articles/s43587-021-00104-9
Abstract:
Luminal epithelial cells in the human mammary gland lose lineage fidelity as they age, exhibiting markers typically found in myoepithelial cells. We believe that loss of lineage fidelity is a common symptom of epithelia that is predisposed to cancer start. We show in this work that histologically normal breast tissue from younger women who are vulnerable to breast cancer due to a germline mutation in the BRCA1, BRCA2, or PALB2 genes displays accelerated aging characteristics. These include a basal differentiation bias or lack of differentiation of cKit+ progenitors, proportionally increased luminal epithelial cells that acquired myoepithelial markers, reduced proportions of myoepithelial cells, and decreased proportions of myoepithelial cells. The opposite lineage, inflammatory and cancer-related pathways, are transcriptionally enriched in high-risk luminal and myoepithelial cells. Regardless of the precise underlying genetic or age-dependent risk or the associated breast cancer subtype, we have found breast-aging hallmarks that suggest convergent biology of cancer susceptibility.
Main:
For sporadic breast cancers, the largest risk factor is becoming older1. Despite the apparent link between aging and cancer susceptibility, just one out of every eight women in the United States develops breast cancer. The majority of these breast cancers are sporadic and have unknown causes. Only 5–10% of breast cancers are caused by a few germline mutations in genes including BRCA1, BRCA2, CHEK2, ATM, TP53, and PALB2. Women with these germline mutations are not only diagnosed with breast cancer more frequently but also at a younger age2. For example, BRCA1 mutation (BRCA1mut) carriers are predicted to have a lifetime risk of breast cancer diagnosis of more than 70%2. We hypothesized that because the bulk of these germline mutations are in genes that produce essential DNA damage-repair proteins, random physiochemical damages may accumulate more often, leading to an acceleration of biological age and phenotypic aging3.
The mammary gland is a bilayered epithelium with a secretory luminal epithelial cell layer that expresses keratin 19 (KRT19) and an outer layer of contractile KRT14-expressing myoepithelial cells. Myoepithelial cells are epithelial cells with basal characteristics that are hypothesized to inhibit tumor growth4,5. A basement membrane divides the epithelial compartment from the adipose-rich stromal compartment, which is bordered by a bilayered epithelium. The quantity of adipose tissue in the stroma rises with age, whereas connective tissue decreases6. The proportions of luminal cells rise, myoepithelial cell proportions fall, and tyrosine kinase receptor cKit-expressing progenitors with a basal differentiation bias concentrate in the epithelia6,7. The acquired expression of myoepithelial proteins such as the intermediate filament KRT14 is a remarkable age-dependent alteration in the luminal epithelia (refs. 6,7,8). This age-dependent condition is known as loss of lineage fidelity, in which luminal epithelia acquire certain myoepithelial features while still retaining luminal epithelial cell characteristics8. Because cKit progenitors and more mature luminal cells are the potential breast cancer cells of origin6,9,10,11,12, the phenotypic alterations that occur in the luminal epithelia deserve special study. It’s unclear if fidelity loss is specifically linked to aging or more widely linked to cancer risk.
The capacity of cells to shift between distinct metastable states by utilizing the epithelial-to-mesenchymal transition (EMT) and stem-cell-related gene programs13 is known as epithelial plasticity. Cancers take advantage of epithelial flexibility, which is crucial for development. Basal-like breast tumors, which are often triple negative, have a lot of epithelial plasticities. 14,15. Basal-like breast tumors are renowned for their aggressiveness and resistance to chemotherapy, and they are prevalent in high-risk women with BRCA1 mutations16,17. Increased flexibility and the capacity to shift between progenitor, basal, and luminal states14 have been linked to aggressive behavior. We hypothesize that luminal cells’ age-related loss of lineage fidelity is a kind of epithelial plasticity and that their acquisition of basal characteristics is a step toward greater cancer susceptibility. In the average-risk (AR) population, age is a significant risk factor for breast cancer, but carriers of specific germline gene variations are at a much higher risk, even if they are premenopausal and chronologically young. Loss of lineage fidelity in luminal epithelia is a biological emergent characteristic of mammary epithelia that is vulnerable to cancer start and is increased in high-risk (HR) women, according to the researchers.
We examined pathologically normal breast tissue from prophylactic mastectomies of women with germline mutations in breast cancer-susceptibility genes to see if the breast epithelial changes we previously identified as age-dependent are associated with breast cancer susceptibility due to predisposing mutations. Epithelia from clinically confirmed, germline, HR breast tissue showed an increase of luminal cells that expressed KRT14 when compared to AR controls. Regardless of the precise germline mutation, differentiation experiments revealed that cKit-enriched (cKit+) progenitors from HR epithelia had a basal bias. HR luminal and myoepithelial cells differ from AR cells in terms of transcriptional enrichment for aging, inflammatory, and senescence gene signatures. Based on the different underlying germline mutations, the enrichment for several distinct gene signatures among HR epithelia showed that the cells generate mutation-specific microenvironments. Predisposing germline mutations accelerate aging processes in mammary epithelia, resulting in compositional alterations that impair the tissue’s ability to inhibit cancer start and increase the pool of cancer cells of origin, according to our findings.