Abstract A122: Role of cellular senescence in breast cancer prevention and treatment

Abstract

Abstract Most studies on cellular senescence (CS) have been conducted in vitro on normal and tumor cell lines by employing antitumor agents, irradiation, or by modulating activity of specific genes. These different approaches lead to DNA damage, gene instability, telomerase inhibition, and/or chromatin alterations that primarily affect p53 - p21 signaling. Little is known whether cancer prevention/therapy agents; tamoxifen, SERMs, aromatase inhibitors and retinoids/rexinoids, which do not directly damage DNA, can also induce CS in normal mammary tissues, premalignant lesions and tumors and the molecular mechanisms involved. To determine the effects of the above agents on CS, normal MEC, breast cancer cell lines, mammary carcinogenesis models that produce ER+ and ER- tumors, xenograft tumor models, as well as frozen sections from breast carcinomas were employed. A double labeling procedure was developed that first identifies senescent cells (SC) by SA-β-Gal reaction and then the expression of genes associated with CS, among them; p53, p21, p16, gH2A.X, pRb, RARβ2, HIPg and telomerase activity. siRNA technology was used to assess the role of p21 and RARβ2 expression in mediating the senescence program of retinoids and rexinoids. In addition to CS, cell proliferation and apoptosis were also examined. We found that SC were mostly detected in hyperplastic and premalignant lesions and rarely in tumors. In MNU-mammary carcinogenesis model, tamoxifen, vorazole (an aromatase inhibitor), DHEA, retinoids [all-trans retinoic acid (atRA), 9-cis-retinoic acid (9cRA), 4-hydroxyphenyl-retinamide (4-HPR) and rexinoids (LDG1069), in addition to inhibition of cell proliferation also induced CS. Doses of the above agents that induced CS were similar to those inhibiting cell proliferation, but lower to those leading to apoptosis. CS induced by tamoxifen, DHEA, aromatase inhibitors and rexinoids was associated with p21 and p16 up-regulation and with decrease in telomerase activity. Retinoids and rexinoids were also efficacious inducers of CS in both, MNU and MMTV-Neu mammary carcinogenesis models, that produce ER+ and ER- mammary tumors. The alterations in the above senescence associated target genes was also confirmed in MCF-7, T47D, MDA-MD-231 and BT474 breast tumor cell lines. Our data suggests that in addition to cell proliferation and apoptosis, CS can be also used as potential biomarker of response in breast cancer preclinical and clinical studies, as well as in testing the efficacy of potential preventive and antitumor agents. Supported by KG100509 grant from Susan G Komen Breast Cancer Foundation Citation Format: Anne Shilkaitis, Albert Green, Tohru Yamada, Konstantin Christov. Role of cellular senescence in breast cancer prevention and treatment. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Breast Cancer Research: Genetics, Biology, and Clinical Applications; Oct 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2013;11(10 Suppl):Abstract nr A122.