title: 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.
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.
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Stefano
authors.initials: S
authors.lastname: Rossetti
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: MingQiang
authors.initials: M
authors.lastname: Ren
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Nicolo
authors.initials: N
authors.lastname: Visconti
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Francesca
authors.initials: F
authors.lastname: Corlazzoli
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Gagliostro
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Giulia
authors.initials: G
authors.lastname: Somenzi
authors.affiliation: The State University of New York at Buffalo, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
authors.forename: Jin
authors.initials: J
authors.lastname: Yao
authors.affiliation: The State University of New York at Buffalo, Center of Excellence in Bioinformatics and Life Sciences, Buffalo, NY 14203, USA.
authors.forename: Yijun
authors.initials: Y
authors.lastname: Sun
authors.affiliation: Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Sacchi
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D001940:Breast / Q000473:pathology*; D001943:Breast Neoplasms / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D044127:Epigenesis, Genetic; D004847:Epithelial Cells / Q000502:physiology; D005260:Female; D006801:Humans; D009024:Morphogenesis; D009361:Neoplasm Invasiveness; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D000072482:Retinoic Acid Receptor alpha / Q000235:genetics*; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; D019869:Phosphatidylinositol 3-Kinases
keywords: RARA; breast cancer; epigenetic transcriptional regulation; mammary epithelial cell fate decisions; retinoic acid (RA)