title: Bexarotene induces cellular senescence in MMTV-Neu mouse model of mammary carcinogenesis.
abstract: Previous studies have shown that retinoids and rexinoids can prevent breast cancer in animal models and in women with increased risk of developing the disease. The cellular effects of these vitamin A analogues have been primarily associated with induction of differentiation and inhibition of proliferation. In this study, we tested the hypothesis that bexarotene (LGD1069, Targretin), a rexinoid, can not only inhibit cell proliferation but also induce cellular senescence in mammary epithelial cells, premalignant lesions, and tumors of the MMTV-Neu model of mammary carcinogenesis, which develops estrogen receptor-negative tumors. Mice with palpable mammary tumors were treated for 4 weeks with bexarotene at 80 or 40 mg/kg body weight, and senescent cells were determined by SA-β-Gal assay. Bexarotene decreased in a dose-dependent manner the multiplicity of premalignant lesions and tumors, and this was associated with inhibition of cell proliferation and induction of cellular senescence and apoptosis. By double labeling of senescent cells, first by SA-β-Gal and then by antibodies against genes related to cellular senescence, we found that p21, p16, and RARβ, but not p53, were upregulated by bexarotene in mammary tumors and in breast cancer cell lines, suggesting involvement of multiple signaling pathways in mediating the senescence program of rexinoids. These findings indicate that, in addition to cell proliferation and apoptosis, cellular senescence could be used as a potential biomarker of response in breast cancer prevention and therapy studies with rexinoids and possibly with other antitumor agents.
authors: Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, Chicago, Illinois, USA.
authors: Anne
authors: A
authors: Shilkaitis
authors: Laura
authors: L
authors: Bratescu
authors: Albert
authors: A
authors: Green
authors: Tohru
authors: T
authors: Yamada
authors: Konstantin
authors: K
authors: Christov
mesh_terms: D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage*; D000077610:Bexarotene; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000235:genetics; D016922:Cellular Senescence / Q000187:drug effects*; D005260:Female; D018734:Genes, erbB-2; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology*; D008324:Mammary Tumor Virus, Mouse; D051379:Mice; D008822:Mice, Transgenic; D013764:Tetrahydronaphthalenes / Q000008:administration & dosage*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D016588:Anticarcinogenic Agents; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene