Gary G. Schwartz

Elevated serum levels of calcium are frequently observed in advanced breast cancer, but data on serum calcium and breast cancer characteristics at the time of breast cancer diagnosis are limited. We conducted a cross-sectional study of 555 women with newly-diagnosed, untreated breast cancer in North Dakota. We examined the relationship between tumor size, serum calcium and other clinical characteristics of breast tumors, including age and hormone receptor status, using multiple linear regressions. Tumors that were estrogen receptor negative tended to be associated with higher serum calcium levels (p = 0.07). We observed a significant positive correlation between tumor volume and serum calcium levels (adjusted for patient age, body mass index, hormonal receptors, stage at diagnosis, and grade). The association between tumor volume and serum calcium was limited to post-menopausal women. Our finding that postmenopausal women with larger breast tumors had significantly higher serum calcium levels is consistent with a calciotropic effect of early breast cancer in postmenopausal women.

High dietary intake of calcium has been classified as a probable cause of prostate cancer, although the mechanism underlying the association between dietary calcium and prostate cancer risk is unclear. The vitamin D receptor (VDR) is a key regulator of calcium absorption. In the small intestine, VDR expression is regulated by the CDX‐2 transcription factor, which binds a polymorphic site in the VDR gene promoter. We examined VDR Cdx2 genotype and calcium intake, assessed by a food frequency questionnaire, in 533 African–American prostate cancer cases (256 with advanced stage at diagnosis, 277 with localized stage) and 250 African–American controls who participated in the California Collaborative Prostate Cancer Study. We examined the effects of genotype, calcium intake, and diet–gene interactions by conditional logistic regression. Compared with men in the lowest quartile of calcium intake, men in the highest quartile had an approximately twofold increased risk of localized and advanced prostate cancer (odds ratio [OR] = 2.20, 95% confidence interval [CI] = 1.40, 3.46), with a significant dose–response. Poor absorbers of calcium (VDR Cdx2 GG genotype) had a significantly lower risk of advanced prostate cancer (OR = 0.41, 95% CI = 0.19, 0.90). The gene–calcium interaction was statistically significant (p = 0.03). Among men with calcium intake below the median (680 mg/day), carriers of the G allele had an approximately 50% decreased risk compared with men with the AA genotype. These findings suggest a link between prostate cancer risk and high intestinal absorption of calcium. © 2012 American Society for Bone and Mineral Research

The apparently high yield of testis tumors (25%) in rats exposed long-term to Ochratoxin A (OTA) is uninterpretable without data on tumor yield in unexposed rats. Conversely, our demonstration that prenatal exposure to OTA induces DNA adducts in the testes of newborn mice and the absence of these adducts in the testes of mice not exposed prenatally to OTA, is evidence for the presumptive carcinogenicity of OTA in the testis. Together with recent data showing that prenatal exposure to OTA depresses expression of DMRT1, a tumor suppressor gene in the testis, our findings suggest that OTA may be a cause of testicular cancer.

Background: Prospective epidemiologic studies indicate that the risk for advanced prostate cancer is increased among men with high levels of serum calcium. Because serum calcium levels are influenc...

Ochratoxin A (OTA) is a nephrotoxin and carcinogen that is associated with Balkan endemic nephropathy and urinary tract tumors. OTA crosses the placenta and causes adducts in the liver and kidney DNA of newborns. Because the testis and kidney develop from the same embryonic tissue, we reasoned that OTA also may cause adducts transplacentally in the testis. We tested the hypothesis that acute exposure to OTA, via food and via exposure in utero, causes adducts in testicular DNA and that these lesions are identical to those that can be produced in the kidney and testis by the consumption of OTA. Adult mice received a single dose of OTA (from 0–1,056 µg/kg) by gavage. Pregnant mice received a single i.p. injection of OTA (2.5 mg/kg) at gestation day 17. DNA adducts were determined by ³²P-postlabeling. Gavage-fed animals sacrificed after 48 hours accumulated OTA in kidney and testis and showed DNA adducts in kidney and testis. Some OTA metabolites isolated from the tissues were similar in both organs (kidney and testis). The litters of mice exposed prenatally to OTA showed no signs of overt toxicity. However, newborn and 1-month old males had DNA adducts in kidney and testis that were chromatographically similar to DNA adducts observed in the kidney and testis of gavage-fed adults. One adduct was identified previously as C8-dG-OTA adduct by LC MS/MS. No adducts were observed in males from dams not exposed to OTA. Our findings that in utero exposure to OTA causes adducts in the testicular DNA of male offspring support a possible role for OTA in testicular cancer.

Experimental and clinical data implicate calcium and parathyroid hormone (PTH) in the development of prostate cancer. However, epidemiologic data on the role of these variables in prostate health are sparse. We examined the relationship between serum levels of calcium, PTH, and prostate-specific antigen (PSA), an established marker of prostate growth, in a large, population-based study using multivariate linear regression. We studied 1,273 men in National Health and Nutrition Survey 2005 to 2006 who were ≥40 years of age and who were without clinical prostate cancer. Adjusted for age, race, body mass index, and serum levels of 25-hydroxyvitamin D, serum levels of PTH were significantly positively correlated with serum PSA (P = 0.01). Serum levels of PTH and calcium each were correlated significantly with free PSA (P = 0.05 and 0.008, respectively). The percentage of men who had elevated serum levels of PTH (PTH, ≥66 pg/mL) was significantly greater among African American men (19.2 versus 9.6%, P = 0.04). Compared with men whose PTH was at the lower end of the reference range, the predicted PSA for men with a PTH of 66 pg/mL was increased 43%. These findings support the hypothesis that serum calcium and serum PTH stimulate prostate growth in men without clinical prostate cancer and have implications for the use of PSA as a screening tool for prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(11):2869–73)

We recently reported a significant positive association in the National Health and Nutrition Examination Survey between high levels of total calcium in serum, measured prospectively, and risk of fatal prostate cancer. To confirm this, we examined associations between total and ionized serum calcium and prostate cancer mortality in an independent cohort, the Third National Health and Nutrition Examination Survey. Twenty-five prostate cancer deaths occurred over 56,625 person-years of follow-up. Compared with men in the lowest tertile of total serum calcium, the multivariate-adjusted relative risk for death from prostate cancer for men in the highest tertile was 2.07 (95% confidence interval, 1.06-4.04). For ionized serum calcium, the physiologically active fraction of total serum calcium, the relative risk for men in the highest tertile was 3.18 (95% confidence interval, 1.09-9.28). These findings support the hypothesis that serum calcium is a prospective biomarker of fatal prostate cancer. (Cancer Epidemiol Biomarkers Prev 2009;18(2):575–8)

We examined the association between serum calcium levels and the risk for prostate cancer using a prospective cohort, the National Health and Nutrition Examination Survey (NHANES) and the NHANES Epidemiologic Follow-up Study. Eighty-five incident cases of prostate cancer and 25 prostate cancer deaths occurred over 46,188 person-years of follow-up. Serum calcium was determined an average of 9.9 years before the diagnosis of prostate cancer. Comparing men in the top with men in the bottom tertile of serum calcium, the multivariable-adjusted relative hazard for fatal prostate cancer was 2.68 (95% confidence interval, 1.02-6.99; P_trend = 0.04). For incident prostate cancer, the relative risk for the same comparison was 1.31 (95% confidence interval, 0.77-2.20; P_trend = 0.34). These results support the hypothesis that high serum calcium or a factor strongly associated with it (e.g., high serum parathyroid hormone) increases the risk for fatal prostate cancer. Our finding of a >2.5-fold increased risk for men in the highest tertile of serum calcium is comparable in magnitude with the risk associated with family history and could add significantly to our ability to identify men at increased risk for fatal prostate cancer. (Cancer Epidemiol Biomarkers Prev 2008;17(9):2302–5)