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Breast ductal carcinoma in situ (DCIS) has been typically recognized by pathologists on the basis of aberrant mammary duct morphology. Thus, there are increasing efforts to detect DCIS biomarkers and druggable targets. In this study we focused on the molecular mechanism involving Annexin A8 (ANXA8), a Ca 2+ and phospholipid binding protein, which is regulated by all-trans Retinoic Acid (RA), and it is highly expressed in breast DCIS tissue samples relative to atypical ductal hyperplasia, and normal breast tissue. Using a panel of human mammary epithelial HME1 cell lines that share a common protein signature, and develop in vitro three dimensional (3D) "DCIS-like" amorphous structures, we identified by bioinformatics analysis protein-miRNA pairs, potentially involved in mammary morphogenetic mechanisms, including the ANXA8 mechanism. HME1 cells with genetic mutations hampering the physiological RA regulation of the RA receptor alpha (RARA) transcriptional function, but retain the RARA function controlling the PI3KCA-AKT signaling, develop 3D "DCIS-like" amorphous structures with upregulated ANXA8. Consistently, ectopic ANXA8 expression, by affecting the RARA transcriptional function, induced HME1 DCIS-like amorphous acini expressing phosphorylated AKT (P-AKT). Apparently, a RA-RARA-ANXA8 feedback loop fosters a vicious circle of aberrant morphogenesis. Interestingly, a few miRNAs regulated by RA are predicted to target ANXA8 mRNA. These miRNAs are candidate components of the RA-RARA-ANXA8 mechanism, and their deregulation might induce DCIS initiation.

3D Mammary Epithelial Cell Models: A Goldmine of DCIS Biomarkers and Morphogenetic Mechanisms