BERKELEY, CA (UroToday.com) - Prostate cancer cells have a propensity to metastasize to bone causing substantial morbidity and mortality. In particular, there is preferential localization to areas of high bone turnover, but the mechanisms are still unclear. The calcium sensing receptor (CaSR) plays an important role in calcium homeostasis and has also been shown to have oncogenic properties independent of this role. CaSR is expressed on prostate tumor cells, and its activation causes the release of parathyroid hormone-releasing protein leading to bone resorption and further calcium release, which could create an environment favorable to metastatic growth and promote tumor-bone interactions.[1, 2, 3] In our nested case-control study we prospectively examined the association of common genetic variation across the CaSR with prostate cancer incidence, and in particular fatal prostate cancer. We genotyped 18 single nucleotide polymorphisms (SNPs) and conducted both a multi-marker gene-level analysis and analyses for each of the individual SNPs. We also assessed whether these association varied by dietary calcium intake and plasma 25-hydroxy-vitamin D (25(OH)D) levels.
We found that the association of genetic variation in CaSR was specific to lethal prostate cancer (defined as cancers with bone metastases at diagnosis or follow-up and/or prostate cancer-specific death); we did not see any associations with overall prostate cancer. This is consistent with a mechanism where CaSR may be involved in driving progression to lethal cancers through increasing metastatic potential of tumors. In vitro work has indicated that CaSR increases cell proliferation in prostate cancer cell lines in cells with higher metastatic potential.[4] We also observed stronger associations for lethal prostate cancer and the CaSR SNPs among men with lower 25(OH)D levels. Vitamin D is an important factor in calcium homeostasis, and bone remodeling and vitamin D deficiency in animal studies stimulated prostate cancer growth in bone.[5] The CaSR gene contains a vitamin D response element that can up-regulate its expression.[6]
While our findings should be replicated in additional large cohort studies, there are several unique and important aspects of our study. First, we used lethal prostate cancer as the main endpoint. In today’s age of prostate specific antigen screening, a large proportion of men will not die from their prostate cancer. Thus, lethal prostate cancer is the most clinically relevant endpoint to study and it has been established that risk factors for lethal prostate cancer are generally different than those for overall prostate cancer incidence.[7] Few cohorts have the long-term follow-up necessary to assess this endpoint due to the long natural history of prostate cancer. Secondly, the role of vitamin D in prostate cancer is controversial, with many studies finding no association with total prostate cancer incidence. We recently observed a strong inverse association of vitamin D and lethal prostate cancer.[8] Our current study’s finding that the association between genetic polymorphisms in CaSR and lethal prostate cancer is modified by vitamin D lends additional support for a causal role of vitamin D in prostate cancer progression. Third, we implemented a logistic kernel-machine model to assess the joint effect of common variation across the CaSR gene, improving our power to detect an overall association compared with individual SNP analyses. Finally, our study provides additional insight into the complex pathology underlying bone metastases. Follow-up studies that further explore the role of the CaSR in the formation of bone lesions and prostate metastases could yield new opportunities for risk stratification, prevention, and therapies.
References:
- Saidak Z, Mentaverri R, Brown EM. The role of the calcium-sensing receptor in the development and progression of cancer. Endocr. Rev. Apr 2009;30(2):178-195.
- Saidak Z, Boudot C, Abdoune R, et al. Extracellular calcium promotes the migration of breast cancer cells through the activation of the calcium sensing receptor. Exp. Cell Res. Jul 15 2009;315(12):2072-2080.
- Yano S, Macleod RJ, Chattopadhyay N, et al. Calcium-sensing receptor activation stimulates parathyroid hormone-related protein secretion in prostate cancer cells: role of epidermal growth factor receptor transactivation. Bone. Sep 2004;35(3):664-672.
- Liao J, Schneider A, Datta NS, McCauley LK. Extracellular calcium as a candidate mediator of prostate cancer skeletal metastasis. Cancer Res. Sep 15 2006;66(18):9065-9073.
- Zheng Y, Zhou H, Ooi LL, Snir AD, Dunstan CR, Seibel MJ. Vitamin D deficiency promotes prostate cancer growth in bone. The Prostate. Jun 15 2011;71(9):1012-1021.
- Canaff L, Hendy GN. Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D. J. Biol. Chem. Aug 16 2002;277(33):30337-30350.
- Giovannucci E, Liu Y, Platz EA, Stampfer MJ, Willett WC. Risk factors for prostate cancer incidence and progression in the health professionals follow-up study. Int. J. Cancer. Oct 1 2007;121(7):1571-1578.
- Shui IM, Mucci LA, Kraft P, et al. Vitamin D-related genetic variation, plasma vitamin D, and risk of lethal prostate cancer: a prospective nested case-control study. J. Natl. Cancer Inst. May 2 2012;104(9):690-699.
Written by:
Irene M. Shui and Kathryn M. Wilson as part of Beyond the Abstract on UroToday.com. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.
Department of Epidemiology Harvard School of Public Health, Boston, MA USA
Common genetic variation of the calcium sensing receptor and lethal prostate cancer risk - Abstract
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