The main goal of this grant proposal is to determine the role of cellular senescence (CS) as a potential intermediate (surrogate) endpoint in mammary cancer prevention by rexinoids. We will use MMTV-erbB2 transgenic mice, which spontaneously develop estrogen receptor negative (ER-) mammary premalignant lesions and tumors and ER- cancer cell lines that differentially express p53, p21 and p16. LG100268 will be used as an inhibitor of mammary carcinogenesis. LG100268 is a rexinoid with low toxicity that has shown an inhibitory effect on mammary carcinogenesis in transgenic mice and rats and is currently being used in various preclinical and clinical trials for the prevention and treatment of breast and other types of cancer. The long term objective of this study is to assess the feasibility of CS as an intermediate (surrogate) endpoint biomarker for efficacy in clinical trials for prevention and treatment of breast cancer. We will test the hypothesis that CS, like apoptosis and cell cycle arrest, is an independent biomarker of response of ER- mammary premalignant lesions and tumors to rexinoids and that the genetic background of mammary epithelial cells (MECs) may determine their decision to initiate a senescent program, stop proliferating, or die by apoptosis. To test this hypothesis we will: (i) assess the efficacy of LG100268, to induce CS in normal mammary epithelial cells (MECs), premalignant lesions (CIS), and carcinomas in MMTV-erbB2 transgenic mice which spontaneously develop ER- mammary tumors;(ii) Determine the role of p53, p16Ink4a and p21Waf1/Cip1 expression in mediating the senescent program of rexinoids in mammary premalignant and tumor cells. Senescent cells (SC) will be determined by SA-?-Gal staining and by other methods. The effect of rexinoids on cell proliferation and apoptosis will be also examined. The data obtained in these studies may have implication in the potential use of CS as an intermediate (surrogate) endpoint for efficacy in cancer prevention and therapy studies, in identifying novel molecular targets for rexinoids, and in selecting patients with premalignant lesions and tumors that would benefit the most from clinical trials with rexinoids.
This study will provide preclinical data for the potential effect of rexinoids on cellular senescence in mammary premalignant and malignant lesions and cells. An animal model of mammary carcinogenesis will be employed that simulates the development and progression of erbB2/New human breast cancer, which comprises about 20-25% of all breast carcinomas in women. LG100268 is a rexinoid with low toxicity that has shown efficacy in the prevention and treatment of ER+ and ER- breast cancer in animals
| Shilkaitis, Anne; Green, Albert; Christov, Konstantin (2015) Retinoids induce cellular senescence in breast cancer cells by RAR-? dependent and independent pathways: Potential clinical implications (Review). Int J Oncol 47:35-42 |
| Shilkaitis, Anne; Bratescu, Laura; Green, Albert et al. (2013) Bexarotene induces cellular senescence in MMTV-Neu mouse model of mammary carcinogenesis. Cancer Prev Res (Phila) 6:299-308 |
