1. Vitamin D and breast cancer risk: epidemiological evidence Tom Rohan Dept. of Epidemiology and Population Health Albert Einstein College Of Medicine

2. Vitamin D & breast cancer - rationale Main actions of 1,25(OH) 2 D are receptor-mediated VDRs present in normal breast tissue 1,25(OH) 2 D has anti-proliferative effects on & promotes differentiation of breast cancer cells In MCF-7 cells, vitamin D & analogues: - induce cell cycle arrest & apoptosis - down-regulate ER expression - limit responsiveness to mitogenic effects of 17β- estradiol - limit induction of PR

3. Vitamin D & breast cancer – sources of epidemiologic evidence Ecologic studies Vitamin D and breast density VDR polymorphisms and breast cancer risk Circulating vitamin D levels and breast cancer risk Dietary and supplemental vitamin D intake and risk

4. Ecologic studies Several ecologic studies of sunlight/solar radiation exposure & breast cancer incidence/mortality Synthesis in skin resulting from exposure to sunlight (esp. UV-B) is major source of endogenous production of vitamin D Few food sources of vitamin D

5. Vitamin D and breast cancer – ecologic evidence Gorham, Int J Epidemiol, 1990 R = -0.75 p value = 0.001

6. Ecologic studies Limitations: Measurements averaged over individuals Confounding Hypothesis-generating

7. Mammographic density

8. Extensive dense breast tissue confers 4-5 fold increase in subsequent breast cancer risk Mammographic density can be modified Represents a potential biological marker for assessing risk-modifying effects of dietary & supplemental factors

9. Vitamin D & mammographic density 3 studies showed inverse association in premenopausal women (2 for vitamin D from foods only; 1 for foods + supplements) 1 of these showed inverse association in postmenopausal women also (foods only) All studies reasonably large All studies cross-sectional In one study, association independent of sunlight exposure but weakened by adjusting for calcium

10. Vitamin D Receptor (VDR) VDR is a nuclear transcription regulating factor Mediates cell growth & differentiation effects of vitamin D Expressed in normal & malignant breast cells Genetic polymorphisms in VDR may affect VDR gene expression & protein function

11. VDR polymorphisms and breast cancer risk Fok1, Bsm1, Apa1, Taq1, Poly(A) Fok1 is functional; Others in strong LD – functional significance less clear - length polymorphism Poly(A) may affect transcriptional efficiency/stability of VDR mRNA 14 studies to date – 3 nested case-control studies; others hospital/population-based Results inconsistent – sample size, selection bias, confounding, differences in extent of LD

12. Circulating levels and tissue production of vitamin D Circulating vitamin D levels related to dietary intake and cutaneous synthesis of vitamin D Active form (1,25(OH) 2 D) produced by hydroxylation of major circulating form (25(OH)D) 1,25(OH) 2 D produced in breast (& kidney, colon, prostate) by 1α hydrox. of 25(OH)D Extent of production depends on available 25(OH)D Low circulating 25(OH)D might impair local production of 1,25(OH) 2 D in breast

13. Circulating vitamin D levels and breast cancer risk 25(OH)D: - Case-control study – strong inverse association - Nested case-control – weak inverse association 1,25(OH) 2 D: - Case-control study – strong inverse association - Nested case-control study – no association Bias in retrospective studies Single measure of 25(OH)D  short-term exposure

14. Dairy products and breast cancer Constituents that may increase risk: - total and saturated fat - contaminants in milk (e.g., pesticides) - growth factors (e.g., IGF-I) Constituents that may decrease risk: - conjugated linoleic acid - calcium & vitamin D ~50 studies of dairy product intake and breast cancer risk – results inconsistent

15. Dietary and supplemental vitamin D intake and breast cancer risk 10 studies – 5 case-control; 5 cohort Diet in adolescence: - 2 cohort studies – results null - 1 case-control study - inverse association with use of vitamin D supplements (& sunlight exposure) between ages 10-19 and 20-29

16. Dietary and supplemental vitamin D intake and breast cancer risk Diet in adulthood – case-control studies mostly null – cohort studies: - John (1999) – solar radiation/dietary intake –  risk - Shin (2002) –  risk in premenop. women for total/dietary vit. D, & supp. vit D in those with low dietary intake - no assoc. in postmenop. women - McCullough (2005) – postmenop. women – no. assoc. with total/dietary vit. D -  risk with dietary vit. D in those in areas with low UV exposure

17. Summary of current evidence Ecologic studies – inverse association Breast density – inverse association VDR polymorphisms – inconclusive Circulating vitamin D levels – inconclusive Vitamin D intake - inconclusive

18. Conclusions Establishing independent association for vit. D intake from observational epi. studies challenging Few food sources of vit. D/UV-B major source Need studies that: - use validated methods to quantify intensity & duration of sunlight exposure - assess other factors that influence vit. D status - skin pigmentation, sunscreen/protective clothing, medical conditions, medications

19. Conclusions (cont.) Comprehensive assessment of vit D. status also requires assessment of determinants of circulating 25(OH)D & 1,25(OH) 2 D, including: glycemic index – may affect cellular uptake of calcium retinol – can antagonize vit. D actions BMI – inversely assoc. with serum 25(OH)D – deposition in fat Associations may vary by VDR genotype.