Research Papers:

Tracing anti-cancer and cancer-promoting actions of all-trans retinoic acid in breast cancer to a RARα epigenetic mechanism of mammary epithelial cell fate

Stefano Rossetti _, MingQiang Ren, Nicolo Visconti, Francesca Corlazzoli, Vincenzo Gagliostro, Giulia Somenzi, Jin Yao, Yijun Sun and Nicoletta Sacchi

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Oncotarget. 2016; 7:87064-87080. https://doi.org/10.18632/oncotarget.13500

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Stefano Rossetti1, MingQiang Ren1, Nicolo Visconti1, Francesca Corlazzoli1, Vincenzo Gagliostro1, Giulia Somenzi1, Jin Yao2, Yijun Sun2, Nicoletta Sacchi1

1Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA

2The State University of New York at Buffalo, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA

Correspondence to:

Nicoletta Sacchi, email: [email protected]

Keywords: retinoic acid (RA), RARA, epigenetic transcriptional regulation, mammary epithelial cell fate decisions, breast cancer

Received: September 02, 2016     Accepted: October 28, 2016     Published: November 22, 2016


A hallmark of cancer cells is the ability to evade the growth inhibitory/pro-apoptotic action of physiological all-trans retinoic acid (RA) signal, the bioactive derivative of Vitamin A. However, as we and others reported, RA can also promote cancer cell growth and invasion. Here we show that anticancer and cancer-promoting RA actions in breast cancer have roots in a mechanism of mammary epithelial cell morphogenesis that involves both transcriptional (epigenetic) and non-transcriptional RARα (RARA) functions. We found that the mammary epithelial cell-context specific degree of functionality of the RARA transcriptional (epigenetic) component of this mechanism, by tuning the effects of the non-transcriptional RARA component, determines different cell fate decisions during mammary morphogenesis. Indeed, factors that hamper the RARA epigenetic function make physiological RA drive aberrant morphogenesis via non-transcriptional RARA, thus leading to cell transformation. Remarkably, also the cell context-specific degree of functionality of the RARA epigenetic component retained by breast cancer cells is critical to determine cell fate decisions in response to physiological as well as supraphysiological RA variation. Overall this study supports the proof of principle that the epigenetic functional plasticity of the mammary epithelial cell RARA mechanism, which is essential for normal morphogenetic processes, is necessary to deter breast cancer onset/progression consequent to the insidious action of physiological RA.

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