## 4 Vitamin D Resistance  
The impact of a defective VDR, either as expression or activity, is crucial for the biological effects of vitamin D. Indeed, in many pathological conditions vitamin D resistance occurs, due to three distinct possible defects: (i) Lack of VDR expression, (ii) calcitriol deficiency or increased vitamin D catabolism, or (iii) repression of transcriptional activity of vitamin D-VDR-RXR complex. Vitamin D resistance can be inherited or de novo acquired; in the former case is caused by the mutation of VDR or RXR genes or the genes involved in calcitriol activation, catabolism, and signaling, in the latter case the resistance can be environment-dependent. Concerning the inherited resistance, most of the mutations observed where discovered either in VDR or RXR domains and are considered the main cause of the recessive form of rickets (type I) [45].  
The prevalent mechanism of vitamin D acquired resistance present in pathological conditions, especially in cancer, involves the transcriptional repression of VDR. Although VDR is expressed in most cell types, it was shown that its expression is progressively reduced during the progression of different cancer types, such as skin, breast, and prostate cancer [46; 47; 48]. A decrease in the expression of VDR is associated with a late stage disease and a poor prognosis in urothelial bladder cancer, while a high VDR expression correlates with better survival in non-small cell lung cancer patients [46; 49]. An impairment of VDR expression can be explained as a strategy used by tumor cells to counteract the tumor-suppressive effects of vitamin D. A first molecular mechanism that allows tumor cells to inhibit VDR expression consists in the over expression of the Snail family of transcriptional repressors. Indeed, in breast and colon cancer cells Snail1 and -2 can bind DNA near the promoter regions of VDR gene recruiting co-repressors that inhibit VDR transcription [50]. Furthermore, it was shown that the expression of K-Ras and H-Ras mutants, respectively in human and mouse colon cancer cells, suppresses VDR transcription [51]. The repression of VDR due to epigenetic mechanisms is discussed in the next section.  
Another very common cause of resistance is the increase in vitamin D catabolism due to the up-regulation of the enzyme CYP24A1. In breast cancer CYP24A1 has been proposed as an oncogene because it was found amplified and it was correlated with poor prognosis and a decreased survival rate [52]. Colon, prostate, lung, ovarian, cervical, and many other types of cancer have shown an up-regulation of this catabolic enzyme that positively correlates with advanced cancer stages and is associated with a poor outcome [53; 54; 55].  
Cancer is not the only pathological condition characterized by the acquisition of vitamin D resistant phenotype. From infectious diseases such as tuberculosis or HIV (human immunodeficiency virus), to autoimmune disorders as systemic lupus erythematosus, rheumatoid arthritis, or [PERSON]'s disease, many immunopathologies are often associated with a lack of VDR expression after a long activation of T-helper cells or in the presence of VDR polymorphisms [56]. Since vitamin D resistance plays a primary role in multiple pathological conditions, a great effort has been put into the research of possible treatments. One of the most promising approaches seems to be based on the epigenetic modulation.