Oncotarget: Inhibition of HAS2 and hyaluronic acid production by 1,25-Dihydroxyvitamin D3 in breast cancer

Oncotarget Volume 11, Issue 30 reported that 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.

Here the Oncotarget authors confirmed that 1,25D3 reduces both HAS2 gene expression and hyaluronic acid synthesis in multiple models of breast cancer.

HAS2 expression and HA production are elevated in immortalized human mammary epithelial cells induced to undergo epithelial-mesenchymal transition 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.

Dr. JoEllen Welsh from The University at Albany said "1,25-Dihydroxyvitamin D3 (1,25D3), the high affinity ligand for the nuclear VDR, regulates multiple cancer processes (cell cycle, apoptosis, migration, invasion) in vivo and in vitro, however the specific gene targets and mechanisms that mediate these effects are unclear."

These authors previously established invasive mammary tumor cell lines from wild-type and VDR knockout mice and demonstrated that the VDR is necessary for 1,25D3 mediated anti-cancer signaling in vitro and in vivo.

One of the VDR down-regulated genes was Has2, an enzyme that synthesizes the polysaccharide hyaluronic acid.

Figure 10: Clinical relevance of HAS2 in TCGA METABRIC dataset of human breast cancer. (A) Oncoprint showing genomic alterations in VDR, HAS1, HAS2, and HAS3 in 1904 human breast tumors. Each column of light grey bars in this scheme represents one case of human breast cancer; colored bars indicate specific types of genomic alterations as indicated in the legend. (B) Kaplan Meier analysis of overall survival in METABRIC dataset stratified by HAS2 alterations. (C) HAS2 alterations according to breast cancer subtype. (D) Correlation between HAS2 and GFPT2 expression. All data were calculated from publicly accessible METABRIC database at cBio Cancer Genomics Portal.

1,25D3 treatment reduced Has2 expression 50–70% in VDR positive cells but was without effect in VDR negative cells.

Collectively, these data suggest that survival and outgrowth of CD44 cancer stem cells are dependent on continued HA synthesis through HAS2 activity.

This concept predicts that disruption of HA-CD44 signaling would inhibit disease progression in patients whose tumors overexpress HAS2. In the studies reported here the authors assessed whether 1,25D3 regulates HAS2 in cellular models of human breast cancer, and whether suppression of HAS2 by 1,25D3 is sufficient to inhibit HA synthesis in the context of aggressive disease.

The Welsh Research Team concluded in their Oncotarget Research Paper that although VDR may frequently be retained in breast tumors, many women with breast cancer are vitamin D deficient.

Therefore, attention to vitamin D status and/or vitamin D supplementation may be necessary to ensure appropriate VDR transcriptional activity in tumors.

In support of a beneficial effect of vitamin D in cancer, the most recent meta-analysis of vitamin D trials including VITAL indicated a significant reduction in cancer mortality with vitamin D supplementation.

The data suggest that the anti-tumor actions of vitamin D may be mediated in part through suppression of HA signaling. In the METABRIC dataset, HAS2 was overexpressed in 27% of all breast tumors, with highest frequency in those subtypes with poor prognosis.

Since HA content is increased during breast cancer progression and elevations in HAS2 and HA correlate with poor prognosis, further studies to evaluate the association of vitamin D signaling and the HA pathway in aggressive human breast cancers are of significant interest.

The data suggest that combining vitamin D supplementation with therapies that target HA signaling or the hexosamine pathway may be therapeutically beneficial.

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DOI - https://doi.org/10.18632/oncotarget.27587

Full text - https://www.oncotarget.com/article/27587/text/

Correspondence to - JoEllen Welsh - jwelsh@albany.edu

Keywords - vitamin D, hyaluronic acid, hyaluronan synthase, HAS2, breast cancer

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