Inhibition of HAS2 and hyaluronic acid production by 1,25-Dihydroxyvitamin D3 in breast cancer
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Carmen J. Narvaez1,2,*, Erika LaPorta1,3,*, Samantha Robilotto1, Jennifer Liang4 and JoEllen Welsh1,2,3
1 University at Albany Cancer Research Center, Rensselaer, NY, USA
2 Department of Environmental Health Sciences, University at Albany, Rensselaer, NY, USA
3 Department of Biomedical Sciences, University at Albany, Rensselaer, NY, USA
4 Department of Biochemistry, Queen’s University, Kingston, ON, Canada
* Joint first authors
Keywords: vitamin D; hyaluronic acid; hyaluronan synthase; HAS2; breast cancer
Received: February 21, 2020 Accepted: April 10, 2020 Published: July 28, 2020
1,25-Dihydroxyvitamin D3 (1,25D3) induces growth arrest and apoptosis in breast cancer cells in vivo and in vitro, however the exact mechanisms are unclear. Although the vitamin D receptor (VDR), a ligand dependent transcription factor, is required for growth regulation by vitamin D, the specific target genes that trigger these effects are unknown. Genomic profiling of murine mammary tumor cells with differential VDR expression identified 35 transcripts that were altered by the 1,25D3-VDR complex including Hyaluronan Synthase-2 (Has2). Here we confirmed that 1,25D3 reduces both HAS2 gene expression and hyaluronic acid (HA) synthesis in multiple models of breast cancer. Furthermore, we show that the growth inhibitory effects of 1,25D3 are partially reversed in the presence of high molecular weight HA. HAS2 expression and HA production are elevated in immortalized human mammary epithelial cells induced to undergo epithelial-mesenchymal transition (EMT) through stable expression of TGFβ, SNAIL or TWIST and in those expressing oncogenic H-RASV12, indicating that deregulation of HA production may be an early and frequent event in breast tumorigenesis. 1,25D3 also reduces HA secretion and acts additively with an HA synthesis inhibitor to slow growth of cells expressing TGFβ, SNAIL and TWIST. Analysis of mammary gland and tumors from Vdr knockout mice suggest that loss of VDR is associated with enhanced HAS2 expression and HA production in vivo. These data define a novel role for 1,25D3 and the VDR in control of HA synthesis in epithelial tissues that likely contributes to its anti-cancer actions.
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