Plasma 25-hydroxy vitamin D concentrations, vitamin D receptor genotype and breast cancer risk in a UK Caucasian population
Introduction
In addition to its well-established role in maintenance of calcium homeostasis, the active form of the hormone vitamin D, 1α, 25-dihydroxy vitamin D (1,25(OH)2D) is known to have potent anti-proliferative effects in many cancer cell types, including breast and prostate cancers [1]. The anti-cancer properties of 1,25(OH)2D include induction of differentiation and apoptosis in addition to inhibition of cancer cell growth. 1,25(OH)2D is produced by hydroxylation of the major circulating form of vitamin D, 25-hydroxy vitamin D (25(OH)D), a reaction catalysed by the renal enzyme 25-hydroxy vitamin D-1α-hydroxylase, which has recently been found to be expressed in a variety of tissues such as colon [2], breast, cervix and ovary [3]. This presents the possibility that the non-classical effects of vitamin D may be linked to extra-renal expression of this enzyme and paracrine/autocrine production of 1,25(OH)2D.
Laboratory studies have demonstrated that 1,25(OH)2D and its synthetic analogues inhibit growth and induce apoptosis in cultured breast cancer cells and in animal models of breast cancer [4]. Epidemiological and laboratory studies have suggested that adequate vitamin D status may play a role in reducing breast cancer risk. Vitamin D status is dependent upon cutaneous synthesis initiated by solar radiation and also on dietary intake; a reduction in one or both sources leads to vitamin D insufficiency. Population studies have suggested that risk of fatal breast cancer in the major urban areas is inversely related to the intensity of local sunlight [5] and reduced risk of breast cancer has been observed in women with high dietary vitamin D intake [6]. Circulating levels of 25(OH)D are directly related to dietary vitamin D intake and cutaneous synthesis. The capacity to generate 1,25(OH)2D locally in the breast will be dependent on the availability of 25(OH)D as substrate for 1α-hydroxylase. Thus it could be postulated that low circulating concentrations of 25(OH)D impair generation of 1,25(OH)2D within breast tissue, increasing risk of tumour development.
1,25(OH)2D exerts both its anti-cancer effects and its effects on calcium homeostasis by binding to its intracellular receptor, the vitamin D receptor (VDR). Upon ligand binding VDR undergoes a conformational change that causes its dissociation from transcriptional repressors and binding to transcriptional activators. VDR then acts as a transcription factor that binds to specific elements within target genes, which ultimately leads to changes in gene transcription [7]. There are a number of polymorphisms in the gene encoding the VDR (VDR), some of which have been linked to risk of certain types of cancer, including prostate [8], [9], colorectal [10] and renal carcinoma [11]. A single nucleotide polymorphism (SNP) in the 3′ end of the gene, BsmI, present in two forms denoted B and b, has previously been linked to breast cancer risk; in a study of Caucasian women, we have found that women with the bb genotype had almost twice the risk of breast cancer compared with those with the BB genotype [12]. This study group has been substantially enlarged, and a significant relationship between the VDR polymorphism BsmI and breast cancer risk confirmed [13]. In the present study, we have quantitated circulating 25(OH)D concentrations in matched cases and controls in order to assess the combined effect of the VDR polymorphism and circulating concentrations of 25(OH)D on risk of breast cancer in our population.
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Volunteers
Ethical approval for this study was received from the St. George’s Hospital Ethics Committee. Breast cancer patients and control volunteers were recruited as part of a study investigating VDR genotype and risk of breast cancer. Only Caucasian women were recruited. All gave written informed consent before providing a 10-ml blood sample and answering a brief questionnaire. The questionnaire was used to determine personal information, such as use of hormone replacement therapy (HRT) and menopausal
Characteristics of cases
The median age of the cases was 58 (range 34–84) years. A total of 160 (89.4%) women were post-menopausal, 117 (65.4%) had never used HRT and 126 (70.4%) had no family history of breast cancer. A total of 167 women (93%) had invasive ductal carcinoma and 140 (78%) were oestrogen receptor (ER) positive. The remaining 12 patients had ductal carcinoma in situ (DCIS). A total of 124 (69%) patients received post-operative radiotherapy. Fourteen patients had a local recurrence only and 29 had
Discussion
The major action of vitamin D is to maintain bone mineralisation by promoting absorption of dietary calcium. Vitamin D status is dependent upon cutaneous synthesis initiated by solar radiation and also on dietary intake; a reduction in one or both sources will lead to vitamin D insufficiency. Circulating concentrations of 25(OH)D serve as a useful index of vitamin D status and in vitamin D sufficiency, serum levels range from 50 to 200 nM [14]. Previous studies have investigated the relationship
Conflict of interest statement
None declared.
Acknowledgements
This research was funded by the Breast Cancer Campaign (BCC), the Breast Cancer Research Trust (BCRT) and the World Cancer Research Fund (WCRF). We are grateful to all the women who agreed to take part in this study and to the nurses and doctors at St. George’s Hospital who helped with volunteer recruitment.
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