Abstract P4-11-01: A genetic model of mammary gland fibrosis and cancer risk

Abstract

Abstract Ductal cells of the mammary gland arise from mammary stem cells (MSC) and consist of estrogen receptor a negative (ER-) luminal cells and a small ER+ luminal population. Luminal cells are maintained by the proliferation of ER- luminal progenitor (LP) cells, which are expanded in basal subtype breast cancer. Human breast LP cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Short telomeres resulting from the DNA damage response correlate with aggressive breast cancer phenotypes. Telomeric repeat factor 2 (TRF2) binds to telomeres and protects them from the DNA damage response. TRF2 expression is reduced in most human breast cancers but the phenotypic advantages of this genetic alteration are unknown. To determine the effects of telomere DNA damage on mammary gland function and tumor phenotype, we deleted TRF2 expression in mammary gland epithelium. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. MSC from TRF2 deficient glands were unable to completely regenerate mammary glands following transplantation to cleared fat pads. TRF2 deficient mammary tumors also demonstrated telomere DNA damage response but exhibited rapid onset and increased proliferation. Tumor derived LP cells underwent expansion but exhibited high telomere DNA response and failed to form tumors following transplantation. In contrast, the severely depleted MSC population was highly tumorigenic and maintained telomeres via the ALT mechanism. Telomere DNA damage response in mammary tumors resulted in p53 dependent ER+ cellular differentiation and sensitivity to anti-estrogen therapy. Our results provide a new in vivo model for exploring mechanisms of mammographic density, stem cell differentiation, cancer risk, and therapeutic sensitivity. Citation Format: Wu J, Crowe D. A genetic model of mammary gland fibrosis and cancer risk [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-11-01.