– We have previously shown that Annexin A8 (ANXA8) is strongly associated with the basal-like subgroup of breast cancers, including BRCA1-associated breast cancers, and poor prognosis; while in the mouse mammary gland AnxA8 mRNA is expressed in low-proliferative isolated pubertal mouse mammary ductal epithelium and after enforced involution, but not in isolated highly proliferative terminal end buds (TEB) or during pregnancy. ANXA8 as a potential mediator of quiescence in the normal mouse mammary ductal epithelium, while its expression in basal-like breast cancers may be linked to ANXA8’s association with their specific cells of origin. Annexin A8 (ANXA8), a member of a superfamily of calcium and phospholipid binding proteins, is physiologically expressed in a tissue-specific manner, recent microarray studies reported that ANXA8 was also ectopically expressed in pancreatic cancers. We investigated the molecular mechanism of expression of ANXA8 in cancer cells and its functional role in pancreatic cancer cells. ANXA8 was diversely expressed in human cancer cell lines. Ectopic ANXA8 expression in cancer cells might involve an epigenetic mechanism. ANXA8 might play an important role in calcium fluctuation-mediated HIF-1α transcriptional activation and cell viability. The retinoic acid derivative fenretinide (FR) is capable of transdifferentiating cultured retinal pigment epithelial (RPE) cells towards a neuronal-like phenotype, down-regulation of AnxA8 is both necessary and sufficient for neuronal transdifferentiation of RPE cells and reveal an essential role for AnxA8 as a key regulator of RPE phenotype.