Elizabeth T. Jacobs

Vitamin D and colorectal, breast, and prostate cancers: A review of the epidemiological evidence

Over the past two decades, the question of whether vitamin D has a role in cancer incidence, progression, and mortality has been studied in detail. Colorectal, breast, and prostate cancers have been a particular area of focus; together, these three malignancies account for approximately 35% of cancer cases and 20% of cancer deaths in the United States, and as such are a major public health concern. Herein, we review and synthesize the epidemiological research regarding vitamin D, as measured by the biomarker 25-hydroxycholecalciferol [25(OH)D], and the incidence, progression, and mortality of these cancers. Overall, the results of observational studies of the relationship between 25(OH)D and colorectal cancer have revealed a consistent inverse association for incidence and mortality; while for breast cancer, results have generally demonstrated a relationship between higher 25(OH)D and lower risk for progression and mortality. In contrast, randomized, double-blind clinical trials conducted to date have generally failed to support these findings. For prostate cancer, there is no convincing evidence of an association between 25(OH)D and incidence, and inconsistent data for progression and mortality, though results of one open label clinical trial suggest that supplementation with 4000 IU/d of vitamin D3 may inhibit progression of the disease. Nonetheless, until the results of additional ongoing randomized, double-blind clinical trials are reported, it will be difficult to ascertain if vitamin D itself is related to a reduction in risk for some cancer endpoints, or whether high concentrations of the vitamin D biomarker 25(OH)D may instead serve as a marker for an overall beneficial risk factor profile.

Adherence to Diet and Physical Activity Cancer Prevention Guidelines and Cancer Outcomes: A Systematic Review

Many studies have reported that adherence to health promotion guidelines for diet, physical activity, and maintenance of healthy body weight may decrease cancer incidence and mortality. A systematic review was performed to examine associations between adherence to established cancer prevention guidelines for diet and physical activity and overall cancer incidence and mortality. PubMed, Google Scholar, and Cochrane Reviews databases were searched following the current recommendations of Preferred Reporting Items for Systematic Reviews and Meta-analysis Approach (PRISMA). Twelve studies met inclusion criteria for this review. High versus low adherence to established nutrition and physical activity cancer prevention guidelines was consistently and significantly associated with decreases of 10% to 61% in overall cancer incidence and mortality. Consistent significant reductions were also shown for breast cancer incidence (19%–60%), endometrial cancer incidence (23%–60%), and colorectal cancer incidence in both men and women (27%–52%). Findings for lung cancer incidence were equivocal, and no significant relationships were found between adherence and ovarian or prostate cancers. Adhering to cancer prevention guidelines for diet and physical activity is consistently associated with lower risks of overall cancer incidence and mortality, including for some site-specific cancers. Cancer Epidemiol Biomarkers Prev; 25(7); 1018–28. ©2016 AACR.

CYP24A1 and CYP27B1 Polymorphisms Modulate Vitamin D Metabolism in Colon Cancer Cells

Vitamin D is a well-studied agent for cancer chemoprevention and treatment. Its chief circulating metabolite, 25-hydroxyvitamin D, is converted into the active hormone 1,25-dihydroxyvitamin D (1,25D) by the cytochrome P450 enzyme CYP27B1 in kidney and other tissues. 1,25D is then deactivated by CYP24A1 and ultimately catabolized. Colorectal carcinoma cells express CYP27B1 and CYP24A1 that locally regulate 1,25D with potential implications for its impact on carcinogenesis. While 1,25D inhibits cancer growth, the effects of polymorphic variations in genes encoding proteins involved in 1,25D homeostasis are poorly understood. Using an RXR-VDR mammalian two-hybrid (M2H) biologic assay system, we measured vitamin D metabolite uptake and activation of the vitamin D receptor (VDR) pathway in colon cancer cells that expressed one of five CYP27B1 single-nucleotide polymorphisms (SNP) or four CYP24A1 SNPs. Compared with the wild-type control, four of five CYP27B1 SNPs reduced enzymatic activity, whereas one (V166L) increased activity. For CYP24A1, all tested SNPs reduced enzyme activity. Quantitative real-time PCR analyses supported the results of M2H experiments. The observed SNP-directed variation in CYP functionality indicated that vitamin D homeostasis is complex and may be influenced by genetic factors. A comprehensive understanding of 1,25D metabolism may allow for a more personalized approach toward treating vitamin D-related disorders and evaluating risk for carcinogenesis.

Correlates of high vaccination exemption rates among kindergartens.

OBJECTIVESnThe present study was designed to characterize Arizona schools with high rates of permanent PBE among kindergartners, and to determine the degree to which they aggregate across the state.nnnMETHODSnData for permanent personal belief exemptions (PBE) were accessed through the 2010-2011 kindergarten Immunization Data Report (IDR) from the Arizona Department of Health Services (AZDHS), and were linked to the 2009-2010 data from the National Center of Education Statistics (NCES). Incidence rate ratios (IRR) were calculated using negative binomial regression, and hotspots were identified using Getis-Ord Gi*.nnnRESULTSnSchools with highest proportion of white students compared to the lowest had the highest exemption rates (IRR=14.11; 95% confidence interval [CI], 9.47-21.03); furthermore charter schools and those with low prevalence of free and reduced lunches had significantly higher rates of PBE. Statewide analyses of PBE identified higher rates of permanent PBE in northern vs. southern Arizona, while a more focused examination of the central Arizona region demonstrated a pattern of increased PBE from west to east.nnnCONCLUSIONnIn Arizona, the profile of a high PBE school is that of a charter school attended by predominantly white, higher-income students. The local and statewide hotspots serve as a challenge that requires a multi-faceted approach that calls upon all healthcare professionals. It is important that both local and statewide pockets be targeted by local and state officials either to improve vaccination uptake or to employ careful monitoring to identify outbreaks at their onset.

Selenium supplementation for prevention of colorectal adenomas and risk of associated type 2 diabetes

BACKGROUNDnSelenium supplementation may help to prevent colorectal cancer; as precursors of colorectal cancer, colorectal adenomas are a surrogate for colorectal cancer. Selenium supplementation may increase risk of type 2 diabetes (T2D).nnnMETHODSnThe Selenium and Celecoxib (Sel/Cel) Trial was a randomized, placebo controlled trial of selenium 200 µg daily as selenized yeast and celecoxib 400u2009mg once daily, alone or together, for colorectal adenoma prevention. Men and women between age 40 and 80 years were eligible following colonoscopic removal of colorectal adenomas. The primary outcome was adenoma development. Celecoxib was suspended because of cardiovascular toxicity in other trials, but accrual continued to selenium and placebo. A total of 1621 participants were randomly assigned to selenium or placebo, of whom 1374 (84.8%) were available for analysis. All statistical tests were two-sided.nnnRESULTSnIn the respective placebo and selenium arms of 689 and 685 participants, adenoma detection after medians of 33.6 (range = 0.0-85.1 months) and 33.0 months (range = 0.0-82.6 months) were 42.8% and 44.1% (relative risk [RR] = 1.03, 95% confidence interval [CI] = 0.91 to 1.16, P = .68). In participants with baseline advanced adenomas, adenoma recurrence was reduced by 18% with selenium (RRu2009=u20090.82, 95% CIu2009=u20090.71 to 0.96, P = .01). In participants receiving selenium, the hazard ratio for new-onset T2D was 1.25 (95% CIu2009=u20090.74 to 2.11, P = .41), with a statistically significantly increased risk of selenium-associated T2D among older participants (RRu2009=u20092.21; 95% CIu2009=u20091.04 to 4.67, P = .03).nnnCONCLUSIONSnOverall, selenium did not prevent colorectal adenomas and showed only modest benefit in patients with baseline advanced adenomas. With limited benefit and similar increases in T2D to other trials, selenium is not recommended for preventing colorectal adenomas in selenium-replete individuals.

One-Year Risk for Advanced Colorectal Neoplasia: U.S. Versus U.K. Risk-Stratification Guidelines

BACKGROUNDnGuidelines from the United Kingdom and the United States on risk stratification after polypectomy differ, as do recommended surveillance intervals.nnnOBJECTIVEnTo compare risk for advanced colorectal neoplasia at 1-year colonoscopy among patients cross-classified by U.S. and U.K. surveillance guidelines.nnnDESIGNnPooled analysis of 4 prospective studies between 1984 and 1998.nnnSETTINGnAcademic and private clinics in the United States.nnnPATIENTSn3226 postpolypectomy patients with 6- to 18-month follow-up colonoscopy.nnnMEASUREMENTSnRates of advanced neoplasia (an adenoma ≥1 cm, high-grade dysplasia, >25% villous architecture, or invasive cancer) at 1 year, compared across U.S. and U.K. risk categories.nnnRESULTSnAdvanced neoplasia was detected 1 year after polypectomy in 3.8% (95% CI, 2.7% to 4.9%) of lower-risk patients and 11.2% (CI, 9.8% to 12.6%) of higher-risk patients by U.S. criteria. According to U.K. criteria, 4.4% (CI, 3.3% to 5.4%) of low-risk patients, 9.9% (CI, 8.3% to 11.5%) of intermediate-risk patients, and 18.7% (CI, 14.8% to 22.5%) of high-risk patients presented with advanced neoplasia; U.K. high-risk patients comprised 12.1% of all patients. All U.S. lower-risk patients were low-risk by U.K. criteria; however, more patients were classified as low-risk, because the U.K. guidelines do not consider histologic features. Higher-risk U.S. patients were distributed across the 3 U.K. categories. Among all patients with advanced neoplasia, 26.3% were reclassified by the U.K. criteria to a higher-risk category and 7.0% to a lower-risk category, with a net 19.0% benefiting from detection 2 years earlier. Overall, substitution of U.K. for U.S. guidelines resulted in an estimated 0.03 additional colonoscopy every 5 years per patient.nnnLIMITATIONSnPatients were enrolled 15 to 20 years ago, and quality measures for colonoscopy were unavailable. Patients lacking follow-up colonoscopy or with surveillance colonoscopy after 6 to 18 months and those with cancer or insufficient baseline adenoma characteristics were excluded (2076 of 5302).nnnCONCLUSIONnApplication of the U.K. guidelines in the United States could identify a subset of high-risk patients who may warrant a 1-year clearing colonoscopy without substantially increasing rates of colonoscopy.nnnPRIMARY FUNDING SOURCEnEuropean Union Public Health Programme.

Vitamin D status and breast cancer in Saudi Arabian women: case-control study.

BACKGROUNDnThe role of vitamin D in breast cancer prevention is equivocal. Saudi Arabian women may be at greater risk of vitamin D deficiency because of a darker skin type and a greater likelihood of reduced ultraviolet B radiation exposure. Data regarding the vitamin D status of Saudi Arabian women and its relation to breast cancer risk are lacking.nnnOBJECTIVEnThe purpose of this research was to evaluate the association between circulating concentrations of 25-hydroxyvitamin D [25(OH)D] and breast cancer risk in Saudi Arabian women.nnnDESIGNnA case-control study was conducted among 120 breast cancer cases and 120 controls. The study population was drawn from patients admitted to King Fahd Hospital in Jeddah, Saudi Arabia, from June to August 2009. Participants completed questionnaires on diet and medical history, and serum samples were collected from all women to measure circulating 25(OH)D concentrations.nnnRESULTSnThe participants had a mean age of 47.8 y and a mean body mass index (BMI; in kg/m(2)) of 30.0. Breast cancer cases had significantly lower (mean ± SD) serum concentrations of 25(OH)D (9.4 ± 6.4 ng/mL) than did controls (15.4 ± 12.3 ng/mL; P = 0.001). In comparison with those in the highest category of vitamin D status for this population (≥20 ng/mL), the adjusted ORs (95% CIs) for invasive breast cancer were 6.1 (2.4, 15.1) for women with a serum 25(OH)D concentration <10 ng/mL and 4.0 (1.6, 10.4) for women with a serum concentration of ≥10 to <20 ng/mL (P-trend = 0.0001).nnnCONCLUSIONnAn inverse association exists between serum 25(OH)D concentrations and breast cancer risk in Saudi Arabian women. This trial was registered at clinicaltrials.gov as NCT01817231.

Concentrations of the Vitamin D Metabolite 1,25(OH)2D and Odds of Metabolic Syndrome and its Components

AIMnFew epidemiological studies have investigated the association between circulating concentrations of the active vitamin D metabolite 1,25(OH)2D and metabolic syndrome. We sought to determine whether blood levels of 1,25(OH)2D are associated with metabolic syndrome and its individual components, including waist circumference, triglycerides, blood pressure, and glucose, and high-density lipoprotein. We also investigated these associations for the more abundant precursor vitamin D metabolite, 25(OH)D.nnnMETHODSnParticipants from two completed clinical trials of colorectal neoplasia with available metabolic syndrome data and blood samples for measurement of 1,25(OH)2D (n=1048) and 25(OH)D (n=2096) were included. Cross-sectional analyses of the association between concentrations of 1,25(OH)2D, 25(OH)D, metabolic syndrome, and its components were conducted.nnnRESULTSnA statistically significant inverse association was observed for circulating concentrations of 1,25(OH)2D and metabolic syndrome, with adjusted ORs (95% CIs) of 0.73 (0.52-1.04) and 0.52 (0.36-0.75) for the second and third tertiles of 1,25(OH)2D, respectively (p-trend <0.001). Significant inverse relationships were also observed between 1,25(OH)2D and high triglycerides (p-trend <0.001), and low high-density lipoprotein (p-trend <0.001). For 25(OH)D concentrations, significant inverse associations were found for metabolic syndrome (p-trend <0.01), high waist circumference (p-trend <0.04) and triglyceride levels (p-trend <0.01). Participants with 25(OH)D ≥30 ng/ml and in the highest tertile of 1,25(OH)2D demonstrated significantly lower odds of metabolic syndrome, with an OR (95% CI) of 0.38 (0.19-0.75) compared to those in the lowest category for both metabolites.nnnCONCLUSIONnThese results provide new evidence that the relatively rarely-studied active hormonal form of vitamin D, 1,25(OH)2D, is associated with metabolic syndrome and its components, and confirm prior findings for 25(OH)D. The finding that 1,25(OH)2D is related to high-density lipoprotein, while 25(OH)D is not, suggests that there may be an independent mechanism of action for 1,25(OH)2D in relation to metabolic dysregulation.

Association between circulating concentrations of 25(OH)D and colorectal adenoma: A pooled analysis

The relationship between the biomarker of vitamin D status, 25(OH)D, and the risk for colorectal neoplasia is suggestive but equivocal. Questions remain regarding whether there are differential associations between 25(OH)D and colorectal adenoma by gender, colorectal subsite or features of baseline and recurrent adenomas. We sought to investigate the relationship between 25(OH)D and both baseline and recurrent adenoma characteristics. Our study was conducted among 2,074 participants in a pooled population of two clinical intervention trials of colorectal adenoma recurrence. A cross‐sectional analysis of 25(OH)D and baseline adenoma characteristics and a prospective study of recurrent adenomas and their characteristics were conducted. There was a statistically significant inverse association between the concentrations of 25(OH)D and the presence of three or more adenomas at baseline. Compared to participants with 25(OH)D levels of <20 ng/mL, the adjusted odds ratios (ORs) (95% condifdence intervals [CIs]) were 0.99 (0.70–1.41) for those with concentrations of ≥20 and <30 ng/mL, and 0.73 (0.50–1.06) among participants with levels of ≥30 ng/mL (p‐trendu2009=u20090.05). Baseline villous histology was also significantly inversely related to 25(OH)D levels (p‐trendu2009=u20090.04). Conversely, 25(OH)D concentrations were not associated with overall colorectal adenoma recurrence, with ORs (95% CIs) of 0.91 (0.71–1.17) and 0.95 (0.73–1.24; p‐trendu2009=u20090.85). These findings support the concept that the relationship between vitamin D and colorectal neoplasia may vary by stage of adenoma development.

Resveratrol Potentiates Vitamin D and Nuclear Receptor Signaling

The 1,25‐dihydroxyvitamin D3 (1,25D) hormone is derived from vitamin D generated in skin or obtained from the diet, and binds to and activates the vitamin D receptor (VDR) in target tissues including kidney, colon/small intestine, and bone/muscle. We tested resveratrol for its ability to modulate VDR signaling, using vitamin D responsive element (VDRE) and mammalian 2‐hybrid (M2H) transcriptional system technology. Via VDRE‐based assays in kidney, colon and myoblast cells, VDR‐mediated transcription was activated by resveratrol, and a cooperative effect on transactivation was observed with resveratrol plus 1,25D. The M2H assay revealed a modest, resveratrol‐induced dimerization of VDR with its retinoid X receptor (RXR) heteropartner. Cells treated with both resveratrol and 1,25D displayed synergistic stimulation of VDR–RXR heterodimerization, while resveratrol antagonized rexinoid‐mediated RXR‐RXR homodimerization. Increased transactivation in response to resveratrol was also observed with a subset of other nuclear receptors and their respective cognate responsive elements. Evaluation of wild‐type versus a ligand‐binding domain mutant VDR revealed that hormone‐responsiveness to 1,25D was severely depressed, while the response to resveratrol was only moderately attenuated. Moreover, radiolabeled 1,25D‐displacement assays demonstrated an increase in VDR‐bound 1,25D in the presence of resveratrol. Thus, resveratrol may affect VDR and other nuclear receptors indirectly, likely via the ability of resveratrol to: (1) potentiate 1,25D binding to VDR; (2) activate RXR; and/or (3) stimulate SIRT1, an enzyme known to deacetylate nuclear receptors. The results of this study elucidate a possible pathway for crosstalk between two nutritionally derived lipids, vitamin D and resveratrol, both of which converge on VDR signaling. J. Cell. Biochem. 116: 1130–1143, 2015.