Abstract
Retinoids, derivatives of vitamin A, are key physiological molecules with regulatory effects on cell differentiation, proliferation and apoptosis. As a result, they are of interest for cancer therapy. Specifically, models of breast cancer have varied responses to manipulations of retinoid signaling. This study characterizes the transcriptional response of MDA-MB-231 and MDA-MB-468 breast cancer cells to retinaldehyde dehydrogenase 1A3 (ALDH1A3) and all-trans retinoic acid (atRA). We demonstrate limited overlap between ALDH1A3-induced gene expression and atRA-induced gene expression in both cell lines, suggesting that the function of ALDH1A3 in breast cancer progression extends beyond its role as a retinaldehyde dehydrogenase. Our data reveals divergent transcriptional responses to atRA, which are largely independent of genomic retinoic acid response elements (RAREs) and consistent with the opposing responses of MDA-MB-231 and MDA-MB-468 to in vivo atRA treatment. We identify transcription factors associated with each gene set. Manipulation of the IRF1 transcription factor demonstrates that it is the level of atRA-inducible and epigenetically regulated transcription factors that determine expression of target genes (e.g. CTSS, cathepsin S). This study provides a paradigm for complex responses of breast cancer models to atRA treatment, and illustrates the need to characterize RARE-independent responses to atRA in a variety of models.
Highlights
The evolutionarily-conserved retinoid signaling pathway governs expression of hundreds of genes and regulates a wide variety of fundamental biological processes, including differentiation, cell cycle arrest and cell proliferation[1,2]
The retinoid signaling pathway is often simplified to production of all-trans retinoic acid by aldehyde dehydrogenase 1A (ALDH1A) enzymes, where it translocates to the nucleus and activates nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs)
We have previously characterized that expression of the cancer stem cell marker ALDH1A3 can have opposing effects in two models of triple-negative breast cancer (TNBC): it can promote the growth of MDA-MB-231 xenografts while limiting the growth of MDA-MB-468 xenografts
Summary
The evolutionarily-conserved retinoid signaling pathway governs expression of hundreds of genes and regulates a wide variety of fundamental biological processes, including differentiation, cell cycle arrest and cell proliferation[1,2]. The retinoid signaling pathway is often simplified to production of all-trans retinoic acid (atRA) by aldehyde dehydrogenase 1A (ALDH1A) enzymes, where it translocates to the nucleus and activates nuclear receptors, retinoic acid receptors (RARs) and retinoid X receptors (RXRs) These receptors induce the expression of genes with retinoic acid response elements (RAREs) in their promoters. Cancer stem cells have high levels of ALDH1A enzymes[37,38,39,40,41,42], supporting higher than normal levels of atRA biosynthesis and higher expression of atRA-inducible genes[43]; atRA is used as a differentiating agent which would theoretically eliminate those same cancer stem cells[44,45,46,47] This demonstrates the importance of characterizing cellular responses to atRA in a variety of models, and motivated the current study. We identified known regulators of the retinoid signaling pathway, including dehydrogenase reductase 3 (DHRS3)[50], nuclear receptor interaction protein 1 (NRIP1)[51], and cytochrome p450 family 26A1 (CYP26A1)[52]
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