Page 294 - Vitamin D and Cancer

12 The Vitamin D Signaling Pathway in Mammary Gland and Breast Cancer 281

12.2 Vitamin D and Breast Cancer Links in Populations

12.2.1 Diet, Sunlight Exposure and Breast Cancer Risk

Population studies on vitamin D in relation to chronic diseases such as breast can-
cer are complicated by difficulties in accurately assessing dietary sources (con-
founders include natural foods versus fortified foods, supplement use, intake of D
2
versus D , and calcium status) and estimating the amount of vitamin D generated
3
through sunlight exposure (confounders include lifestyle, latitude, pollution, sun-
screen, skin pigmentation and age). Despite this caveat, the cumulative population
data support an inverse correlation between vitamin D sources (diet or sunlight
exposure) and relative risk of breast cancer. Due to space constraints, only a few of
these studies are highlighted here. An evaluation of the Nurse’s Health Study found
that intakes of dairy products, dairy calcium and vitamin D were inversely associ-
ated with breast cancer risk in premenopausal, but not postmenopausal, women [1].
Similarly, a prospective analysis of breast cancer incidence in relation to vitamin D
intake for over 30,000 participants in the Women’s Health Study indicated that
higher intake of vitamin D was moderately associated with a lower risk of pre- but
not post- menopausal breast cancer [2]. These data are consistent with reports of
inverse associations between vitamin D status and mammographic density in pre-
menopausal women [3, 4]. In addition to dietary vitamin D, [5] demonstrated that
sunlight exposure was associated with reduced risk of breast cancer, and that this
association was dependent on region of residence. A recent follow-up analysis
indicated that the beneficial effect of sunlight exposure on risk was dependent on
skin pigmentation, with significant correlations demonstrated only in women with
fair skin [6]. In larger international studies, a significant inverse correlation between
incident solar radiation and breast cancer rates was confirmed [7–9].

12.2.2 Serum 25-Hydroxyvitamin D and Breast Cancer Risk

Studies which have assessed serum parameters as indicators of vitamin D status in
relation to breast cancer risk have been more consistent. Although confounders
remain (dietary calcium, serum PTH, seasonal influences and assay methodology),
multiple studies have reported significant inverse relationships between relative risk
of breast cancer and serum 25D, the most accurate indicator of vitamin D status
[10–12]. A pooled analysis of data on serum 25D in relation to breast cancer
demonstrated that the highest quintile of serum 25D was associated with a 50%
reduction in breast cancer risk [13]. These data suggested that serum 25D
concentrations above 100 nM may be required to optimize vitamin D signaling in
mammary tissue. This serum 25D concentration is considerably higher than that
necessary for prevention of rickets (approximately 50 nM), suggesting that
prolonged sub-optimal vitamin D status (rather than overt deficiency) is associated