Abstract
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.
Highlights
Epigenetic regulation of transcription plays a significant role in development by regulating major developmental processes, such as X-inactivation, imprinting, and spatiotemporal activation of homeobox genes [1]
As reported in clinical trials for other cancers [36], we found that supraphysiological retinoic acid (RA) exerts paradoxical opposing actions on breast cancer cell growth, depending on the level/functionality of wild type RARA among different breast cancer cell contexts, as well as within the same breast cancer cell context [34, 35, 37]
By global gene expression microarray analysis we found that in breast cancer cells (T47DCtrl) grown under ‘physiological’ (‘physio’) RA culture conditions, many RARA-target genes are in a repressed transcriptional state marked by epigenetic histone modifications, but are transcriptionally responsive to high ‘supraphysiological’ (‘supra’) exogenous RA (10-6M) in the culture medium (Figure 1A, based on Supplementary Table S1, and Supplementary Figure S1)
Summary
Epigenetic regulation of transcription plays a significant role in development by regulating major developmental processes, such as X-inactivation, imprinting, and spatiotemporal activation of homeobox genes [1]. Genome-wide transcriptional regulation in response to precise spatiotemporal variation of physiological RA – which, as a morphogen, determines cell fate in a concentration-dependent manner – has been considered an essential underlying molecular mechanism impacting several facets of development: body plan, organogenesis, morphogenesis, differentiation and tissue homeostasis [2, 4, 11,12,13]. Since generation of precise RA level variation is of essence for determining www.impactjournals.com/oncotarget cell fate decisions during normal development, animal cells evolved mechanisms to regulate transcriptionally genes controlling the metabolism of RA and its precursors, including Retinol/Vitamin A [15]. Animal evolutionary studies identified molecular vestiges of a twomodule RA mechanism encompassing a ‘RA metabolic module’ integrated with a ‘RA signaling module’ regulating gene expression [16]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
