Reversal by RARα agonist Am580 of c-Myc-induced imbalance in RARα/RARγ expression during MMTV-Myc tumorigenesis

Breast cancer research: BCR (Impact Factor: 5.88). 08/2012; 14(4):R121. DOI: 10.1186/bcr3247
Source: PubMed

ABSTRACT INTRODUCTION: Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. Recently, the nuclear retinoic acid receptor (RAR) isotypes , and were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RAR appears to be involved in stem cell compartment expansion, while RAR and RAR are implicated in the subsequent cell differentiation. We found that over-expressing c-Myc in normal mouse mammary epithelium and in a c-Myc-driven transgenic model of mammary cancer, disrupts the balance between RAR and RARin favor of RAR. METHODS: The effects of c-Myc on RAR isotype expression were evaluated in normal mouse mammary epithelium, mammary tumor cells obtained from the MMTV-Myc transgenic mouse model as well human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RAR-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the mouse mammary tumor virus (MMTV)-Myc mouse model of mammary tumorigenesis. RESULTS: Modulation of the RARtoRAR expression in mammary glands of normal mice, oncomice, and human mammary cell lines through the alteration of RAR-target gene expression affected cell proliferation, survival and tumor growth. Treatment of MMTV-Myc mice with the RAR-selective agonist Am580 led to significant inhibition of mammary tumor growth (~90%, P<0.001), lung metastasis (P<0.01) and extended tumor latency in 63% of mice. Immunocytochemical analysis showed that in these mice, RARresponsive genes such as Cyp26A1, E-cadherin, cellular retinol-binding protein 1 (CRBP1) and p27, were up-regulated. In contrast, the mammary gland tumors of mice that responded poorly to Am580 treatment (37%) expressed significantly higher levels of RAR In vitro experiments indicated that the rise in RAR was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RAR pathway is linked to tumor growth inhibition, differentiation and cell death. CONCLUSIONS: The functional consequence of the interplay between c-Myc oncogene expression and the RARto RAR balance suggests that prevalence of RAR over RARexpression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RAR-isotype specific agonists and warrant monitoring during clinical trials.


Available from: Eduardo F Farias, Jan 30, 2014
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