Genetic variations of vitamin D receptor gene and steroid receptors status in breast cancer risk: An updated review

Breast cancer, the most predominant type of cancer reported in females, is a heterogeneous disease classified into various subcategories depending on the presence of hormone receptors. Epidemiological studies show a strong correlation between reduced 1,25 dihydroxy vitamin D3 (1,25(OH)2D3) levels, the active component of vitamin D, and increased breast cancer risk in diverse populations. In a ligand-dependent manner, vitamin D receptor (VDR) transcriptionally modulates its target genes belonging to cell proliferation, differentiation, and apoptosis pathways, thus imparting protective function against cancer growth and progression. The coding and regulatory regions of the VDR gene contain several polymorphisms (BsmI, Fok1, Taq1, Apa1, Cdx2, poly (A), etc.) that modulate its transcription, translation, and mRNA stability. Despite this, research in this area has not yet led to many conclusions. In this review, we analyzed in a systematic way that the association of VDR allelic variants with breast cancer risk among patients from various populations. This analysis has revealed that Fok1, Bsm1, Apa1were to some extent associated with breast cancer risk, Taq1 shows no association, and Cdx2, poly(A), Tru91 gene polymorphisms may be susceptible for breast cancer development. We have highlighted the new insights of the current understanding of molecular mechanisms of the VDR gene polymorphisms related to breast cancer risk and also examined the interaction between VDR polymorphisms and steroid hormone (estrogen, progesterone, and androgen) receptors and their modifying effects on breast cancer risk, cancer severity, progression rate, and disease outcome. Therefore, with a lack of studies and inconsistent results, we recommend that further studies focus on genetic variations of the VDR gene that should be integrated with the assessment of steroid hormone receptor status in breast cancer.