Abstract 836: Rexinoids induce cellular senescence in ER-negative breast cancer cells and in MMTV-Neu mammary tumors

Abstract

Abstract Retinoids and recently rexinoids have been extensively studied as potential cancer preventive agents. Their effects both in vitro and in vivo have been associated with inhibition of cell proliferation via cell cycle regulatory genes/proteins. In previous studies we have shown that retinoids (atRA, 9cRA), in addition to inhibition of cell proliferation, can also induce cellular senescence (CS) in breast cancer cell lines and in an MNU-model of mammary carcinogenesis in rats. We also found that atRA is more efficacious in inducing CS in ER+ than in ER− breast cancer cell lines. Here we examined the role of rexinoids (LGD1069) in inducing CS in ER− breast cancer cell lines and in ER− tumors of the MMTV-Neu model of mammary carcinogenesis in mice. CS was determined by SA-β-Gal staining, colony formation assay, heterochromatin condensation and histone H2AX expression. Cells grown on cover slips were treated for 6 days with 1.0 or 5.0 µM of LGD1069 and senescent cells identified. We found that LGD1069 at 1.0 µM is more efficacious in inducing CS in ER+ MCF-7 and T47D cells, 56% and 42% respectively vs. 14% and 9% in control cells. Normal MCF10A, premalignant MCF10AT, and malignant MDA-MB-231 and MDA-MB-468 cells, which are ER−, required 5.0 µM of LGD1069 to increase CS from 3.0, 6,0, 4.0 and 10.0% in control to 14, 24, 26 and 33% in treated cells. For in vivo studies, MMTV-Neu mice with palpable mammary tumors were treated for 4 weeks with 80 or 40 mg/kg body weight LGD1069, given by gavage. Proliferating cells (BrdU-labeled) in mammary tumors decreased from 9.6±2.3% in control animals (No=13) to 7.4±3.0% (p<0.01) (No=10) and to 5.6±2.5% (p<0.001) (No=12) in high and low dose treated animals, respectively. Senescent cells, as detected by SA-β-Gal staining, were rare in control tumors (0.92±0.23%) and significantly increased in LGD1069, 80 mg/kg treated animals (6.8±4.0%) (p<0.001). LGD1069 was unable to affect apoptosis. Our mechanistic studies suggest involvement of p21, RXRα and RARβ in mediating LGD1069-induced CS in ER− breast cancer cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 836. doi:10.1158/1538-7445.AM2011-836