Abstract 1440: Vitamin D uptake and metabolism in breast cancer tumors: Differential expression of megalin, VDR, CYP27B1 and CYP24A

Diverse studies have concluded that Vitamin D plays a main role of in breast cancer risk. The active metabolite of vitamin D, is a pleiotropic hormone that regulates proliferation, survival, and differentiation of many cell types, through its nuclear receptor VDR. Clinical and epidemiological studies have described the association of decreased serum concentrations of 25-hydroxy-vitamin D with a poor prognosis in patients with breast cancer. The metabolism of vitamin D is meticulously regulated through a complex process, involving the vitamin D-activating enzyme CYP27B1, responsible for the final hydroxylation step to form the active metabolite and CYP24A1, the key enzyme in the inactivation of this metabolite. It is also known that VDR is central for vitamin D-mediated transcription regulation. For all these processes it is necessary that vitamin D enters the cell. In the kidney, internalization of the circulating vitamin D is accomplished by megalin, a membrane receptor for vitamin D, which has not been defined in mammary tissue. Until today reports published in relation to the mechanism of vitamin D uptake and its metabolism are scarce in breast cancer tumors. Our aim was to quantify the expression and to determine the localization of: megalin, VDR, CYP27B1 and CYP24A1 enzymes in breast cancer tumor tissues and normal breast tissue. For this purpose, tissue microarrays of formalin-fixed and paraffin-embedded tumor samples and normal breast tissues were analyzed through immunohistochemistry. This study showed that megalin is localized apically in epithelial cells of normal breast tissue, as previously described in the kidney. On the other hand, in breast cancer tumors megalin expression was diminished. Interestingly, we found that megalin had a different localization in two breast cancer tumor subtypes. In luminal breast cancer tumors, megalin was localized mainly in the cellular membrane whereas in triple negative tumors we observed a cytoplasmic localization. For VDR, CYP27B1 and CYP24A1 our results showed that all these proteins are expressed in normal breast tissues. VDR and CYP24A1 have a heterogeneous expression in relation to tumor subtypes and these are highly expressed in all luminal breast cancer tumors, whereas in triple negative breast cancer subtype its expression was low. Our results suggest that exists an alteration in classical metabolic pathway of vitamin D in the tumor subtypes analyzed of breast cancer. With these results we can suggest that in luminal tumors, which have the better prognosis compared with other subtypes, tumor cells still to respond to vitamin D, while in triple negative subtype, the tumor cells reduce their ability to: uptake, catabolize the active metabolite and respond to vitamin D favoring tumor progression. Citation Format: Gabriela Valarezo, Victoria Ortega-Hernandez, Gonzalo Escobar-Massu, Wanda Fernandez, Maria Paz Marzolo, Pilar Carvallo. Vitamin D uptake and metabolism in breast cancer tumors: Differential expression of megalin, VDR, CYP27B1 and CYP24A [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1440.