Vitamin D and breast cancer risk: epidemiological evidence

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)2D are receptor-mediated • VDRs present in normal breast tissue • 1,25(OH)2D 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. R = -0.75 p value = 0.001 Gorham, Int J Epidemiol, 1990 Vitamin D and breast cancer – ecologic evidence

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

7. Mammographic density

8. Mammographic density • 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)2D) produced by hydroxylation of major circulating form (25(OH)D) • 1,25(OH)2D 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)2D 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)2D: - 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)2D, 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.