Abstract
Abstract Physiological retinoic acid (RA), the bioactive derivative of Vitamin A, is a signal necessary for epithelial cell morphogenesis. During acinar morphogenesis of normal breast epithelial cells in three dimensional (3D) culture, physiological RA activates in a spatiotemporal fashion both genomic and non-genomic RA receptor alpha (RARA) signalings, thus leading to growth-arrested acini with a lumen lined by a layer of polarized cells. In contrast, lack of activation of genomic RARA by physiological RA results in the formation of 3D amorphous acini without lumen and with uncontrolled proliferation of the luminal cells. This is similar to what is observed in early in situ breast cancer lesions, such as ductal carcinoma in situ (DCIS). Different factors that, directly or indirectly, affect genomic RARA in normal breast epithelial cells and, consequently, the morphogenetic action of RA signal, lead to deregulation of members of the Annexin family, including Annexin A8 (ANXA8). Interestingly, upregulation of ANXA8 is sufficient to affect the genomic RARA-mediated RA signaling with consequent development of 3D amorphous acini. Thus, ANXA8 upregulation consequent to functional inhibition of genomic RARA by different factors seems to reinforce through a feedback loop the extent of functional inhibition of genomic RARA itself. It is of significance that ANXA8 upregulation in DCIS does correlate with tumor grade and stage. Acknowledgements: Funding for this study was provided by the NCI R01 CA127614 grant, the Susan Komen Foundation, the Breast Cancer Coalition of Rochester, the Friends for an Earlier Breast Cancer Test, the Terri Brodeur Breast Cancer Foundation. Citation Format: Stefano Rossetti, Wiam Bshara, Johanna Reiners, Francesca Corlazzoli, Austin Miller, Nicoletta Sacchi. Retinoic acid signal and annexins: A vicious circle of breast tumorigenesis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2015-4203
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