Serum Vitamin D and Risk of Breast Cancer within Five Years

By O'Brien, Katie M.; Sandler, Dale P. et al. | Environmental Health Perspectives, July 2017 | Go to article overview

Serum Vitamin D and Risk of Breast Cancer within Five Years


O'Brien, Katie M., Sandler, Dale P., Taylor, Jack A., Weinberg, Clarice R., Environmental Health Perspectives


Introduction

Vitamin D is acquired through both sun exposure and dietary sources. Vitamin [D.sub.3] is synthesized from cutaneous 7-dehydrocholesterol upon exposure to ultraviolet B radiation (Feldman et al. 2014; Holick 2006). Dietary sources of vitamin D include oily fish, fortified milks and cereals, and oral supplements. Vitamin D is metabolized into 25-hydroxyvitamin D [25(OH)D] by the liver and then converted to 1,25-dihydroxyvitamin D [1,25[(OH).sub.2]D] by the kidney and other tissues, including the breast (Welsh et al. 2003).

It is known that 1,25[(OH).sub.2]D has potential anticarcinogenic effects, including regulation of cell growth and proliferation, stimulation of apoptosis, and down-regulation of estrogen receptors (Feldman et al. 2014; Holick 2006; Krishnan et al. 2010; Welsh et al. 2003). In animal models, [D.sub.3] and 1,25[(OH).sub.2][D.sub.3] slowed the growth of existing cancer cells and mammary tumors (Feldman et al. 2014). Levels of 1,25 [(OH).sub.2]D are under tight physiologic control, but levels of the inactive precursor--25(OH)D--vary widely and reflect overall available vitamin D (Holick 2006).

Despite widespread fortification, ~42% of U.S. women have "insufficient" 25(OH)D levels (Forrest and Stuhldreher 2011) (<20 ng/mL (Institute of Medicine of the National Academies 2010)). Extremely high intake of vitamin D [>10,000 international units (IU) daily] for an extended period can cause tissue damage, but adverse effects are extremely rare when intake is <4,000 IU/d (Institute of Medicine of the National Academies 2010). Therefore, if vitamin D has antineoplastic effects, supplementation could offer a safe way to prevent breast cancer, a disease that affects approximately one in eight U.S. women during their lifetimes (Surveillance, Epidemiology, and End Results Program 2015).

The effect of vitamin D supplementation on breast cancer risk was investigated in a clinical trial of 36,282 postmenopausal women randomized to receive placebo or 400 IU vitamin [D.sub.3] plus 1,000 mg calcium daily (Chlebowski et al. 2008). During a mean of 7 y of follow-up, there was no difference in breast cancer rates between treatment arms [hazardratio (HR) =0.96 (95% confidence interval (CI): 0.85, 1.09)]. However, off-protocol self-supplementation was common, and in a reanalysis limited to the 43% of women not taking personal supplements, women randomized to treatment had a statistically significant 18% lower breast cancer rate than women randomized to placebo (Bolland et al. 2011).

Using an alternative approach that considers total vitamin D exposure, numerous case-control (Abbas et al. 2008; Abbas et al. 2009; Chen et al. 2013; Colston et al. 2006; Crew et al. 2009; Janowsky et al. 1999) and cohort (Almquist et al. 2010; Amir et al. 2012; Bertone-Johnson et al. 2005; Chlebowski et al. 2008; Deschasaux et al. 2016; Eliassen et al. 2011; Engel et al. 2010; Freedman et al. 2008; Kim et al. 2014; Kuhn et al. 2013; McCullough et al. 2009; Mohr et al. 2013; Neuhouser et al. 2012; Ordonez-Mena et al. 2013; Rejnmark et al. 2009; Scarmo et al. 2013; Skaaby et al. 2014) studies have evaluated the association between 25(OH)D and breast cancer risk. The estimated strength of association in these observational studies differs across study designs. Case-control studies have reported inverse associations (Abbas et al. 2008; Abbas et al. 2009; Chen et al. 2013; Colston et al. 2006; Crew et al. 2009). Although some prospective cohort studies have also observed inverse associations (Bertone-Johnson et al. 2005; Chlebowski et al. 2008; Engel et al. 2010; Kim et al. 2014; Mohr et al. 2013; Rejnmark et al. 2009), the effects tended to be weaker and not statistically significant. Other prospective studies have reported null results (Almquist et al. 2010; Amir et al. 2012; Deschasaux et al. 2016; Eliassen et al. 2011; Freedman et al. 2008; Kuhn et al. 2013; McCullough et al. 2009; Neuhouser et al. …

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