Abstract 4778: Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer

Abstract

Abstract Human breast luminal progenitor cells exhibit telomere DNA damage, which is associated with mammographic density and increased cancer risk. Telomeric repeat factor 2 (TRF2) protects telomeres from DNA damage response and its expression is reduced in human ductal carcinoma in situ and breast cancers. To determine the relationships between telomere DNA damage, mammary gland biology, and cancer risk we genetically deleted TRF2 expression in the mouse mammary gland. TRF2 conditional null mutant mice also were bred with tumor prone MMTV-Wnt1 animals. Telomere DNA damage response was determined by localization of 53BP1 at telomeres and activation of ATM/Chk2/p53 signaling by western blot. Mammary gland and tumor histopathology were determined by hematoxylin and eosin staining. Cell proliferation and ER+ differentiation was determined by immunohistochemistry. Tumor derived CD24+/CD49f+ mammary stem cells and CD61+ luminal progenitor cells were transplanted to mammary fat pads of immunodeficient mice. Alternative lengthening of telomeres was determined by PML localization at telomeres, chromosome orientation-fluorescence in situ hybridization, and telomere circular DNA amplification. Tumor bearing mice were injected with 15 mg raloxifene to determine mammary tumor anti-estrogen sensitivity. Mammary glands lacking TRF2 expression exhibited increased telomere DNA damage response, histopathological and functional degeneration, and prominent ductal fibrosis. TRF2 deficient mammary tumors exhibited rapid onset and increased proliferation. Tumor derived LP cells failed to form tumors following transplantation. The 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. Telomere DNA damage correlated with estrogen receptor expression in human breast cancer. We concluded that telomere DNA damage resulted in mammary gland fibrosis, reduced tumor latency, ER+ differentiation, and sensitivity to anti-estrogen therapy. Citation Format: Jianchun Wu, David L. Crowe. Telomere DNA damage promotes mammary gland fibrosis and estrogen receptor-positive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4778. doi:10.1158/1538-7445.AM2017-4778