Expression of vitamin D metabolism and signalling components in breast tumours compared to paired normals
K Townsend1, M Guy2, KW Colston2, J Mansi2, MJ Campbell1 & M Hewison1
Recent studies have highlighted a role for vitamin D in the prevention and treatment of breast cancer. The active form of vitamin D, 1,25-dihydroxyvitamin D3 (1,25D3), is a potent antiproliferative/proapoptotic agent and its nuclear receptor (vitamin D receptor, VDR) is well expressed in breast tissue. We have investigated whether or not VDR signalling in breast tumours is due to systemic (renal) 1,25D3 or, as with oestrogens, there is local synthesis of the hormone. Previously we have reported expression of the vitamin D-activating cytochrome P450 1alpha-hydroxylase (CYP27b) in breast cancer cell lines, thereby revealing a potential autocrine mechanism by which environmental/dietary vitamin D status can affect breast tumours. In further studies we have used a panel of 40 matched tumour/normal breast biopsies collected according to local ethical agreement to assess CYP27b status, and other components of vitamin D signalling such as VDR and the inactivating enzyme 24-hydroxylase (CYP24). Using real-time RT-PCR analyses we showed strong expression of CYP27b mRNA in normal breast which was strikingly increased in both oestrogen receptor (ER)+ve (mean = 27 fold increase, P<0.0001, n=28) and ER-ve (mean = 57 fold increase, P<0.0001, n=12) tumours. VDR mRNA was also significantly higher in ER+ve (mean = 6.5 fold increase, P<0.0001, n=28) and ER-ve (mean = 6.1 fold, P<0.01, n=12) tumours. Crucially the 1,25D3-inducible enzyme CYP24 which is weakly expressed in normal breast was only enhanced in tumours with increased CYP27b and VDR, thereby confirming an autocrine pathway for vitamin D signalling in breast cancer. These data show for the first time how dietary/environmental vitamin D status can influence breast tissue responses via local conversion to active 1,25D3 and enhanced VDR expression. The mechanisms involved in upregulation of CYP27b and VDR are currently under investigation but appear to be linked to the grade of tumour as determined by ER status.