Abstract
IntroductionRetinoic 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 α, β and γ were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. For instance, RARγ appears to be involved in stem cell compartment expansion, while RARα and RARβ 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 RARγ and RARα/β in favor of RARγ.MethodsThe 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 as human normal immortalized breast epithelial and breast cancer cell lines. The in vivo effect of the RARα-selective agonist 4-[(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthyl)carboxamido]benzoic acid (Am580) was examined in the MMTV-Myc mouse model of mammary tumorigenesis.ResultsModulation of the RARα/β to RARγ 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 RARα-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, RARα responsive 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 RARγ. In vitro experiments indicated that the rise in RARγ was functionally linked to promotion of tumor growth and inhibition of differentiation. Thus, activation of the RARα pathway is linked to tumor growth inhibition, differentiation and cell death.ConclusionsThe functional consequence of the interplay between c-Myc oncogene expression and the RARγ to RARα/β balance suggests that prevalence of RARγ over-RARα/β expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARα-isotype-specific agonists and warrant monitoring during clinical trials.See related editorial by Garattini et al http://breast-cancer-research.com/content/14/5/111
Highlights
Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues
The functional consequence of the interplay between c-Myc oncogene expression and the RARg to RARa/b balance suggests that prevalence of RARg over-RARa/b expression levels in breast cancer accompanied by c-Myc amplification or over-expression in breast cancer should be predictive of response to treatment with RARaisotype-specific agonists and warrant monitoring during clinical trials
Results c-Myc up-regulates RARg expression leading to downregulation of RARa target gene, cellular retinol-binding protein 1 (CRBP1) We hypothesized that over-expression of c-Myc in the mammary epithelium of mammary tumor virus promoter (MMTV)-Myc transgenic mice leads to up-regulation of RARg and determine if this upregulation happens before the development of palpable tumors
Summary
Retinoic acid signaling plays key roles in embryonic development and in maintaining the differentiated status of adult tissues. The nuclear retinoic acid receptor (RAR) isotypes a, b and g were found to play specific functions in the expansion and differentiation of the stem compartments of various tissues. ATRA functions as a pan-agonist of all three RAR isotypes thereby playing crucial roles in embryonic morphogenesis, cell differentiation and maintenance of adult epithelia [10,11]. These findings together with preclinical, epidemiological and clinical observations [12] have prompted extensive inquiries into ATRA’s potential use as an anti-tumor agent. Interactions between isotypes are dynamic and affected by both intracellular and extracellular environments such as changes in cell signaling induced by oncogenic stress and global kinase activity [33]
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