Vitamin D May Protect against Breast Cancer through the Regulation of Long Noncoding RNAs by VDR Signaling

Abstract

Dietary vitamin D3 has attracted wide interest as a natural compound for breast cancer prevention and therapy, supported by in vitro and animal studies. The exact mechanism of such action of vitamin D3 is unknown and may include several independent or partly dependent pathways. The active metabolite of vitamin D3, 1α,25-dihydroxyvitamin D3 (1,25(OH)2D, calcitriol), binds to the vitamin D receptor (VDR) and induces its translocation to the nucleus, where it transactivates a myriad of genes. Vitamin D3 is involved in the maintenance of a normal epigenetic profile whose disturbance may contribute to breast cancer. In general, the protective effect of vitamin D3 against breast cancer is underlined by inhibition of proliferation and migration, stimulation of differentiation and apoptosis, and inhibition of epithelial/mesenchymal transition in breast cells. Vitamin D3 may also inhibit the transformation of normal mammary progenitors into breast cancer stem cells that initiate and sustain the growth of breast tumors. As long noncoding RNAs (lncRNAs) play an important role in breast cancer pathogenesis, and the specific mechanisms underlying this role are poorly understood, we provided several arguments that vitamin D3/VDR may induce protective effects in breast cancer through modulation of lncRNAs that are important for breast cancer pathogenesis. The main lncRNAs candidates to mediate the protective effect of vitamin D3 in breast cancer are lncBCAS1-4_1, AFAP1 antisense RNA 1 (AFAP1-AS1), metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), long intergenic non-protein-coding RNA 511 (LINC00511), LINC00346, small nucleolar RNA host gene 6 (SNHG6), and SNHG16, but there is a rationale to explore several other lncRNAs.

Keywords: 1,25(OH)2D; VDR; breast cancer; lncRNA; miRNA; vitamin D3.

Figure 1

1,25(OH)2D, a biologically active metabolite of vitamin D, may interact with different transmembrane proteins and affect several signaling pathways that regulate essential phenomena in cancer cells such as apoptosis, differentiation, growth arrest, cell cycle, oncogene and tumor suppressor expression, degradation. These proteins include, but are not limited to, insulin growth factor 1 (IGF1) receptor (IGF1R), epidermal growth factor receptor (EGFR), Wnt/frizzled proteins, E-cadherin, and transforming growth factor-beta (TGFβ). Interactions of 1,25(OH)2D with these proteins lead to a cascade of downstream events resulting in the activation of several signaling pathways, including PI3K/Akt, Ras/Raf/Mek/ERK/MAPK, β-catenin, and SMAD (phosphatidylinositol 3-kinase/AKT serine/threonine kinase, KRAS proto-oncogene/Raf-1 proto-oncogene/mitogen-activated protein kinase kinase 1, SMAD family members, respectively). These signaling pathways may directly regulate the life and death of cancer cells or control the transcription of genes whose products contribute to cancer transformation.

Figure 2

Normal mammary gland progenitors may develop into a normal mammary gland or acquire stem cell-like (SLC) properties to form mammospheres or/and transform into breast cancer stem cells (BCSCs). 1,25(OH)2D, a biologically active metabolite of vitamin D, along with its receptor, VDR, symbolized here as a blue tear, supports the normal development of mammary gland and prevents mammosphere formation by repressing the pluripotency markers OCT4 and KLF-4. Vitamin D may also prevent the conversion of SLC cells into BCSCs by downregulation of other pluripotency markers, including CD44, CD49f, c-Notch1, and pNFκB. Vitamin D may also repress proteins needed for the maintenance of BCSCs, such as Notch1-3, JAG1-2, HES1, and NFκB, preventing the initiation and formation of breast tumors (BTs). Abbreviations are defined in the main text.

Figure 3

Different mechanisms of anticancer action of vitamin D3 (VD3) and its receptor, VDR, supported by long noncoding RNAs (lncRNAs). Vitamin D3 and VDR may decrease the expression of oncogenic lncRNAs and/or increase the expression of their tumor-suppressing counterparts. Vitamin D may activate lncRNAs that degrade BHLH transcription factor, MYC proto-oncogene (c-Myc), causing inhibition of glycolysis in cancer cells, as shown for the maternally expressed gene 3 (MEG3) lncRNA and the colorectal cancer cell line. Vitamin D3/VDR may stimulate a tumor-suppressing lncRNA to disrupt Wnt/β-catenin signaling, resulting in inhibition of migration, proliferation, invasion, and colony formation of cancer cells, as shown for TOPORS antisense RNA 1 (TOPORS-AS1). 1,25(OH)2D may inhibit lncBCAS1-4_1 (BCAS1-4_1), causing inhibition of epithelial/mesenchymal transition (EMT), an important effect in invasion and metastasis.