Abstract
Most studies on cellular senescence (CS) have been performed in vitro by employing cytotoxic agents, irradiation, chromatin and telomerase modulators or by activating certain oncogenes. All these approaches usually lead to DNA damage, gene instability and/or chromatin alterations that primarily affect p53-p21 signaling. Little is known on whether retinoids and rexinoids, which are cell differentiation agents, can also induce CS in vitro and in vivo, and which molecular mechanisms are involved in promoting the senescent phenotype. We reviewed the recent publications on CS induced by retinoids and rexinoids in ER+ and ER− breast cancer cell lines and in corresponding animal models of mammary carcinogenesis which simulate those of human breast cancer. The role of retinoic acid receptors β2 and 5 (RARβ2 and RARβ5) and of receptor independent genes involved in mediating the senescence program of retinoids and rexinoids in ER+ and ER− breast cancer cells is discussed. Potential strategists for clinical implication of CS as biomarker of prognosis and of response to treatment with retinoids, rexinoids and with other cell differentiation and antitumor agents are outlined.
Highlights
Most studies on cellular senescence (CS) have been performed in vitro by employing cytotoxic agents, irradiation, chromatin and telomerase modulators or by activating certain oncogenes
human mammary epithelial cells (HMECs), human breast epithelial cells, 6-9 in vitro passages; MCF10A cell line, immortal, but benign breast epithelial cell line; MCF10AT cell line was generated by stable transfection of MCF10A cells with Ha-Ras oncogene
BCA1, 2, 3, 7 cells are early in vitro passages of breast cancer cells which in biology appear to be closer to primary tumors than to established breast cancer cell lines. aSignificant difference (p
Summary
RARβ has five isoforms: β1, β2, β3, β4 and β5 [8,9]. RARβ2 and RARβ4 isoforms are mostly examined in breast normal and tumor cells, but they may mediate the effect of retinoids in other epithelial cell types [8,10]. Breast cancer cells that express RARβ5 were resistant to retinoids and when treated with atRA did not senesce. There are breast cancer cell lines, which do not express RARβ5, but are resistant to retinoids, suggesting involvement of other transcription factors in mediating the cellular effect of retinoids [19,36,38]. By microarray analysis it was found that both, RARs agonists and antagonists produced similar effects on gene expression, suggesting that the RARE-dependent RARβ2 gene transcription is only a partial component of the retinoid-induced cell growth inhibition and CS [45]. In a recent study it was shown that antisense oligonucleotides against RARβ2 reduced proliferation and caused apoptosis in 3 lung cancer cell lines, but had no effect in 2 other cell lines lacking RARβ2, suggesting that RARβ2 may suppress, and promote proliferative activity of tumor cells and plays a role of proto-oncogene [41]. A combination of retinoids with dimethylating agents, methyltransferase inhibitors or histone deacethylase inhibitors have shown promising efficacy in cell and tumor growth inhibition
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