Profiling of the transcriptional response to all-Trans retinoic acid in breast cancer cells reveals RARE-independent mechanisms of gene expression

Krysta Mila Coyle, Selena Maxwell, Margaret Lois Thomas, Paola Marcato

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23 Citas (Scopus)

Resumen

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.

Idioma originalEnglish
Número de artículo16684
PublicaciónScientific Reports
Volumen7
N.º1
DOI
EstadoPublished - dic. 1 2017

Nota bibliográfica

Funding Information:
Support was provided by grant funding to PM from the Canadian Institutes of Health Research (CIHR, MOP-130304), the Beatrice Hunter Cancer Research Institute (BHCRI), the Breast Cancer Society of Canada, and the QEII Health Sciences Center Foundation. KMC and MLT are supported by studentship or trainee awards from the BHCRI, Canadian Breast Cancer Foundation, and the Canadian Imperial Bank of Commerce. KMC and MLT are supported by CGS-D awards from CIHR, by the Nova Scotia Health Research Foundation, and by the Killam Trusts at Dalhousie University. MLT is supported by NS Research and Innovation Graduate Scholarships.

Publisher Copyright:
© 2017 The Author(s).

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