Modeling vitamin D actions in triple negative/basal-like breast cancer

摘要

Breast cancer is a heterogeneous disease with six molecularly defined subtypes, the most aggressive of which are triple negative breast cancers that lack expression of estrogen receptor (ER) and progesterone receptor (PR) and do not exhibit amplification of the growth factor receptor HER2. Triple negative breast cancers often exhibit basal-like gene signatures and are enriched for CD44+ cancer stem cells. In this report we have characterized the molecular actions of the VDR in a model of triple negative breast cancer. Estrogen independent, invasive mammary tumor cell lines established from wild-type (WT) and VDR knockout (VDRKO) mice were used to demonstrate that VDR is necessary for 1,25-dihydroxyvitamin D3 (1,25D) mediated anti-cancer actions in vitro and to identify novel targets of this receptor. Western blotting confirmed differential VDR expression and demonstrated the lack of ER, PR and Her2 in these cell lines. Re-introduction of human VDR (hVDR) into VDRKO cells restored the anti-proliferative actions of 1,25D. Genomic profiling demonstrated that 1,25D failed to alter gene expression in KO240 cells whereas major changes were observed in WT145 cells and in KO clones stably expressing hVDR (KOhVDR cells). With a 2-fold cutoff, 117 transcripts in WT145 cells and 197 transcripts in the KOhVDR clones were significantly altered by 1,25D. Thirty-five genes were found to be commonly regulated by 1.25D in all VDR-positive cell lines. Of these, we identified a cohort of four genes (Plau, Hbegf, Postn, Has2)that are known to drive breast cancer invasion and metastasis whose expression was markedly down regulated by 1.25D. These data support a model whereby 1,25D coordinately suppresses multiple proteins that are required for survival of triple-negative/basal-like breast cancer cells. Since studies have demonstrated a high prevalence of vitamin D deficiency in women with basal-like breast cancer, correction of vitamin D deficiency in these women represents a reasonable, but as yet untested, strategy to delay recurrence and extend survival. This article is part of a Special Issue entitled '16th Vitamin D Workshop'.