Aging-associated mammary cancer-initiating cells

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Project Summary Our long-term goal is to determine how age-related breast cancer can be prevented; aging is the leading risk for breast cancer and the aging population in the US is steadily expanding. This is an unanswered question largely because the cellular and molecular mechanisms underlying the age-related increase in breast cancer incidence are poorly understood. We recently published that the percentage of CD49fhi mammary stem cells (MaSCs), which can form basal-like mammospheres in vitro and regenerate mammary ducts in vivo, increased steadily during aging. The age-related increase of CD49fhi basal-like cells occurs in both luminal and basal layers, and is associated with increased percentage of mammary ducts with pre-/early-neoplastic lesions in mammary glands of older (25- to 32-month-old) mice. Recent studies showed that MaSC-enriched CD49fhi human mammary epithelial cells are much more prone to be transformed by oncogenes than luminal progenitor cells and mature luminal cells. Indeed, mammary glands regenerated in vivo by older mouse CD49fhi MaSCs showed significantly more hyperplastic and dysplastic lesions than those regenerated by CD49fhi MaSCs from young (2- to 6-month-old) mice. Whole genome RNA sequencing and gene ontology analysis revealed a significantly elevated senescence-associated inflammatory response in older mouse mammary gland cells. Senescent cells are known to have increased mTORC1 activity, which in turn can promote a senescence-associated secretory phenotype. Significantly, in our clinical trial, short-term low-dose rapamycin treatment significantly reduced CD49fhi MaSC frequency and biomarkers associated with cellular senescence, inflammation, and proliferation in breast tissue from postmenopausal patients. These novel observations led us to hypothesize that a positive feedback loop between cellular senescence and increased mTORC1 activity in aging mammary gland promotes the transformation of, and tumorigenesis by, CD49fhi stem-like cells, which can be abrogated by pharmacological interventions. In this proposal, we will test various mouse models of aging and primary organoid cultures of human mammary epithelial cells from pre- and post- menopausal women to identify mechanisms that generate the aging-associated CD49fhi MaSCs and their lineage origin. We will also determine whether long-term intermittent treatment with rapamycin and/or fisetin, a senolytic agent, can abrogate the aberrant CD49fhi MaSCs and prevent mammary tumorigenesis. If successful, our research will reveal the lineage of the aberrant CD49fhi MaSCs, how they were generated, and whether they can be abrogated for long-term by pharmacologic interventions. This work will provide essential information for future clinical studies of using rapamycin-like senolytics for the prevention of breast cancer, particularly the triple negative breast cancer, for which there is no preventive strategy.