# Presentation: 245479

## Vitamin D and breast cancer risk: epidemiological evidence

- Tom Rohan
- Dept. of Epidemiology and Population Health
- Albert Einstein College Of Medicine

## 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

## 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

## 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

## Vitamin D and breast cancer – ecologic evidence

**Notes:**
Per caput average annual total solar energy exposure

## Ecologic studies

- Limitations:
- • Measurements averaged over individuals
- • Confounding
- Hypothesis-generating

**Notes:**
Per caput average annual total solar energy exposure

## Mammographic density

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## 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

## Summary of current evidence

- •	*Ecologic studies* – inverse association
- •	*Breast density* – inverse association
- •	*VDR polymorphisms* – inconclusive
- •	*Circulating vitamin D levels* – inconclusive
- •  *Vitamin D intake *- inconclusive

## 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

## 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.