Vitamin D: And its role in breast cancer

Kaohsiung Journal of Medical Sciences (2018) 34, 423e427

Available online at www.sciencedirect.com

ScienceDirect journal homepage: http://www.kjms-online.com

Review Article

Vitamin D: And its role in breast cancer ¨e a, Maria A. Cuadrado-Cenzual b, Miriam de La Puente-Yagu ˜as c, Marta Herna ´ndez-Cabria c, Marı´a J. Ciudad-Caban c, Luis Collado-Yurrita * a

Obstetrics and Gynecology, Hospital Clı´nico Universitario, San Carlos, Madrid, Spain Laboratory of Medicine, Hospital Clı´nico Universitario, San Carlos, Madrid, Spain c Department of Medicine, Complutense University, Madrid, Spain b

Received 26 November 2017; accepted 7 March 2018

Available online 5 April 2018

KEYWORDS Vitamin D; 25-hydroxyvitamin D; 1,25dihydroxyvitamin D; Breast cancer

Abstract Vitamin D is a fat soluble vitamin that plays a role in calcium and phosphorus homeostasis. Recently, extensive research on its extraskeletal actions has linked vitamin D deficiency to an increased risk of infection, diabetes mellitus types 1 and 2, cardiovascular disease, obesity, asthma, inflammatory bowel disease, colon, breast, prostate and ovarian cancer and some neurological diseases. There are various mechanisms by which vitamin D influences the natural history of cancer. These include the role of vitamin D in the induction of apoptosis, stimulation of cell differentiation, anti-inflammatory and antiproliferative effects and inhibition of angiogenesis, invasion and metastasis. The aim of this review is to clarify the true role of vitamin D in the onset of breast cancer and evolution of the disease after treatment. A further aim is to suggest new research directions to identify indications and requirements for vitamin D supplementation in patients with breast cancer. Copyright ª 2018, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/ by-nc-nd/4.0/).

Introduction Several studies have been conducted to establish the relationship between vitamin D deficiency and different

Conflicts of interest: All authors declare no conflicts of interest. * Corresponding author. Medicine Department (Complutense University of Madrid), Plaza de Ramo ´n y Cajal s/n, 28040 Madrid, Spain. E-mail address: [email protected] (L. Collado-Yurrita).

types of disease, including oncological processes such as breast, colorectal and prostate cancer [1]. Breast cancer is the most frequently occurring tumour among the female population; diagnoses are rising steadily each year [2] and it has become the second leading cause of death in women. Some studies have indicated that diet may exert an influence in approximately 35% of breast cancer cases [3]. Actions such as reduction in alcohol intake and consumption of fats and red meat, together with an increase in the amount of fibre and vitamin D in the diet, may be protective factors against breast cancer.

https://doi.org/10.1016/j.kjms.2018.03.004 1607-551X/Copyright ª 2018, Kaohsiung Medical University. Published by Elsevier Taiwan LLC. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

424 Vitamin D is the precursor of 1,25-dihydroxyvitamin D in the organism, a steroid hormone involved in various processes in the body, including pathways that trigger cancer. The different mechanisms by which 1,25-dihydroxyvitamin D can act protectively against cancer include induction of apoptosis, stimulation of cell differentiation, antiinflammatory and antiproliferative effects and inhibition of angiogenesis, invasion and metastasis [4]. However, a number of factors cause low levels of circulating 25hydroxyvitamin D, such as obesity, low physical activity, age, race, skin type, smoking and living at high latitudes [5e9]. Besides the above-mentioned mechanisms by which vitamin D may exert a protective effect against cancer, it has also been reported that vitamin D may partially facilitate the relationship between physical activity and breast cancer, through exposure to the sun [10,11]. Many hypotheses have been proposed to establish a relationship between concentrations of vitamin D in the body and breast cancer carcinogenesis, both in cell lines and in animal models [12]. A significant reduction in the postmenopausal incidence of breast cancer has been related to high levels of 25-hydroxyvitamin D (25(OH)D) [13]. There is little evidence for a linear causal association between circulating vitamin D concentration and risk of various types of cancer, though the existence of causal clinically relevant effects of low magnitude cannot be ruled out [14,15].

Pathophysiology of vitamin D and its role in breast cancer The main role of vitamin D is as a modulator of calcium homeostasis and osteosynthesis, and it also contributes to the correct functioning of the immune, muscular and nervous systems [16]. Vitamin D is difficult to obtain through the diet because very few foods naturally contain the vitamin, exceptions being the liver of fatty fish and fortified milk. Cutaneous synthesis is the primary natural source of vitamin D [17]. Although there is still no consensus on optimal serum 25OH vitamin D levels, levels below 20 ng per millilitre (ng/mL) have been established as a deficiency, and levels above 150 ng/mL as toxic [18]. All levels between these two extremes are considered normal, but levels between 30 and 60 ng/mL are considered optimal. A high prevalence of vitamin D deficiency can be seen in all races, even in hot climates, being particularly high in African-American women [4]. Vitamin D encompasses a subset of hydrophobic molecules within which the main form is vitamin D3 (cholecalciferol). Cholecalciferol is produced by human skin (the main source of vitamin D) from 7-dehydrocholesterol in response to ultraviolet radiation-B. Mulch, yeast and plants also produce vitamin D (vitamin D2, or ergocalciferol) in response to ultraviolet radiation-B. This plant-derived vitamin D is physiologically active in humans and can be obtained through diet. Both vitamin D2 and D3 are metabolised in the liver to 25-hydroxyvitamin D (25OHD) the main circulating metabolite d and later in the kidney to 1,25-dihydroxyvitamin D (1,25OH2D), the bioactive form of vitamin D and the vitamin D receptor ligand (VDR), through CYP27B1 (1f

M. de La Puente-Yagu ¨e et al. hydroxylase), a mitochondrial enzyme present in proximal renal tubules [4]. Renal CYP27B1 activity correlates inversely with calcium levels, and serum 1,25OH2D concentrations are maintained in the picomoles per litre (pmol/L) range through classical negative feedback mechanisms. Therefore, in normocalcemic conditions, renal CYP27B1 activity is inhibited and instead, 25OHD is metabolised by CYP24 (24-hydroxylase) to 24,25-dihydroxyvitamin D (24,25OHD), a biologically inactive metabolite that is finally converted to calcitroic acid and excreted. The discovery that epithelial breast cells possess the same enzyme system as the kidney renders the effect of vitamin D on breast cancer biologically plausible. Vitamin D can act on cancer through several mechanisms of action, which are summarised in Fig. 1. It is possible that vitamin D plays a role in controlling normal breast cell growth and has the capacity to stop the growth of cancer cells in this location. This protective effect is believed to be largely supported by the chemopreventive actions of 1,25-hydroxyvitamin D (1.25OH2D, or calcitriol), the bioactive form of vitamin D, a well-known calcium regulator [19]. Experimental, preclinical and ecological studies have shown that 1,25OH2D induces differentiation and apoptosis and inhibits cell proliferation and angiogenesis in normal and malignant breast cells. Similar associations have been reported in observational studies. A meta-analysis showed that circulating levels of 1,25OH2D are inversely correlated with the risk of breast cancer [20]. In human cell lines derived from normal breast tissue and in breast cancer cells, 1,25OH2D and other VDR agonists interfere with cell cycle arrest, differentiation and apoptosis, depending on autophagy, the particular type of cell, cellular microenvironment and the activity of other signalling pathways. Particularly in healthy breast cells, calcitriol mediates inhibition of cell growth and differentiation through intervention with vitamin D receptor (VDR). Cells in the mammary gland express CYP27B1 (1f hydroxylase), an enzyme that metabolises vitamin D, converting 25-hydroxyvitamin D (25OHD) to 1,25OH2D, an active metabolite. In support of this notion, the CYP27B1 enzyme regulates development in the mouse mammary gland, with highest levels being found during pregnancy and lactation. In addition, human mammary cells cultured from normal breast tissue express VDR, CYP27B1 and the megalin-cubilin complex. This complex is present in the plasma membrane of epithelial cells of the kidney proximal tubule, as a major glycoprotein uptake complex with a nutritional, catabolic and resorption function, promoting fixation of the complexes formed between 25OHD and its binding protein DBP (vitamin D binding protein). After fixation, 25OHD detaches from DBP and passes into the mitochondria, where it becomes 1,25OH2D. In vitro, concentrations of 25OHD within the range found in human circulation (35e100 nM) inhibit growth of human mammary epithelial cells. At higher concentrations, 25OHD protects MCF-12F breast epithelial cells against cell stressors, including hypoxia, serum deprivation, oxidative stress and apoptosis induction. In mouse mammary gland cell cultures, 25OHD prevents the induction of preneoplastic lesions caused by chemical carcinogens.

Vitamin D: And its role

Figure 1.

425

Summary of the mechanisms of action of vitamin D in the breast cancer.

Although limited in scope, these data suggest that a vitamin D deficiency sufficient to reduce the availability of substrate for CYP27B1 and limit production of 1,25OH2D could result in deregulation of tumour suppressor pathways triggered by VDR. When incubated with physiological concentrations of 25hydroxyvitamin D (25OHD), human mammary cells synthesise 1,25OH2D in sufficient quantity to mediate growth inhibition. However, the concentrations of 1,25OH2D necessary to mediate these effects against cancer (100 nmol/L) are well above the physiological range and are associated with undesirable side effects in vivo. Based on these considerations, it is unlikely that 1,25OH2D acts at systemic level to regulate the growth of mammary cells in vivo. However, identification of CYP27B1 in skin, colon, prostate and breast suggests that when generated locally, 1,25OH2D might act in an autocrine or paracrine manner to protect cells against cancerous transformation. VDR expression is dynamically regulated in the mammary gland throughout the reproductive cycle and is necessary for proper glandular development during puberty, pregnancy and breast involution. In mammary gland cell cultures, VDR agonists, including 1,25OH2D, inhibit ductal proliferation induced by oestrogens and VDR-dependent branching and protect against chemically induced pre-neoplastic lesions. Compared with glands from normal mice, the glands of mice without VDR expression exhibit accelerated development during puberty and pregnancy and reduced apoptosis during post-lactation involution, indicating that VDR acts to regulate the proliferation, differentiation and apoptosis of breast tissue in a physiological context. In contrast with CYP27B1, CYP24A1 expression is not usually detectable in non-cancer cells in the absence of VDR activity, but is highly induced by supplemental treatment with 1,25OH2D. The relative activity of CYP27B1 and CYP24A1 will determine whether VDR is activated or vitamin D is catabolised from 25OHD. In human mammary cells and culture cells of murine organs, 25OHD induces transcription of VDR, suggesting that at baseline, CYP27B1 activity predominates over CYP24 activity, resulting in the net conversion of 25OHD to 1,25OH2D. The data above support the notion that circulating 25OHD attached to DBP is internalised by normal mammary

cells and becomes 1,25OH2D, which interacts with VDR in the same place or in adjacent cells to maintain differentiation and quiescence in the breast epithelium. This hypothesis predicts that the interruption of any of the multiple steps in the transport, metabolism or function of 25OHD could contribute to the development or progression of breast cancer [21]. In short, the components of the endocrine signalling system of vitamin D that are definitively expressed in normal human mammary gland include VDR, CYP27B1, CYP24A1 and megalin. The expression of most of these genes is altered in conjunction with the development of breast cancer, usually through epigenetic mechanisms. Although data linking vitamin D status to the development of breast cancer in the human population are still too inconsistent to form a basis for dietary recommendations, the concentration range of 25OHD (10e100 nM) that exerts beneficial effects on mammary epithelial cells can be achieved in human serum through diet or supplementation and is not associated with adverse side effects. Furthermore, some research suggests that women with low levels of vitamin D present a higher risk of breast cancer. Breast cancer is a heterogeneous disease and it is possible that vitamin D only affects certain subtypes of breast cancer [22]. Although there is still much to learn about the mechanisms by which breast cells process and respond to 25OHD, the available data are consistent with a protective role of this vitamin D metabolite with respect to breast cancer.

Relationship between vitamin D and breast cancer in menopause A 2013 review paper examined 9 articles linking levels of vitamin D and postmenopausal breast cancer, which included 5206 patients with these characteristics compared with 6450 controls [23], suggest that the association of circulating 25(OH)D with breast cancer risk differed a) by menopausal status, and b) nonlinearly by dose. Also a modest inverse association between 25(OH)D and breast cancer risk was observed among postmenopausal women. The same was not the case in women of childbearing age. Furthermore, there is suggestive evidence of a nonlinear inverse association between circulating 25(OH)D and

426 postmenopausal breast cancer risk, specifically at or above a threshold of 27 ng/mL. Although no detailed studies have established a relationship between menopause and the risk of breast cancer, it is known that two phenomena occur in this stage of a woman’s life. One of these is adult weight gain and obesity, which favours an increase in circulating oestrogens and entails increased risk of hormone-dependent breast cancer, [24e26]. Supplementation with vitamin D can reduce the risk of breast cancer in these women since it can downregulate the expression of oestrogen receptors and attenuate the synthesis and signal of these hormones [27]. Although 20 ng/mL is considered a sufficient dietary level of vitamin D for 97% of the population according to Institute of Medicine (IOM) guidelines, it should be borne in mind that the normal range is for bone health, not for the extraskeletal effects of the vitamin [28]. The most widespread recommendation to achieve adequate or high levels of circulating vitamin D is supplementation at 1000 International Units per day (IU/d), to obtain levels of 35 ng/mL [29e31]. Several studies of vitamin D supplementation have been conducted in patients with adjuvant or neoadjuvant chemotherapy for breast cancer; these have found increased levels of circulating vitamin D but with wide variability due to factors such as sun exposure or changes in the type of nutrition [32e34]. More research is clearly required to elucidate the possible mechanisms of action of vitamin D as regards this effect.

Funding Medicine Dp. Faculty of Medicine Complutense University of Madrid Spain.

References [1] Garland C, Garland F, Gorham E, Lipkin M, Newmark H, Mohr S, et al. The role of vitamin D in cancer prevention. Am J Public Health 2006;96:252e61. [2] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127:2893e917. [3] Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981;66:1191e308. [4] Feldman D, Krishnan AV, Swami S, Giovannucci E, Feldman BJ. The role of vitamin D in reducing cancer risk and progression. Nat Rev Cancer 2014;14:342e57. [5] Brock KE, Graubard BI, Fraser DR, Weinstein SJ, StolzenbergSolomon RZ, Lim U, et al. Predictors of vitamin D biochemical status in a large sample of middle-aged male smokers in Finland. Eur J Clin Nutr 2010;64:280e8. [6] Chan J, Jaceldo-Siegl K, Fraser GE. Determinants of serum 25 hydroxyvitamin D levels in a nationwide cohort of blacks and non-Hispanic whites. Cancer Causes Control 2010;21:501e11. [7] Jorde R, Sneve M, Emaus N, Figenschau Y, Grimnes G. Crosssectional and longitudinal relation between serum 25hydroxyvitamin D and body mass index: the Tromso study. Eur J Nutr 2010;49:401e7.

M. de La Puente-Yagu ¨e et al. [8] Lagunova Z, Porojnicu AC, Lindberg F, Hexeberg S, Moan J. The dependency of vitamin D status on body mass index, gender, age and season. Anticancer Res 2009;29: 3713e20. [9] Millen AE, Wactawski-Wende J, Pettinger M, Melamed ML, Tylavsky FA, Liu S, et al. Predictors of serum 25hydroxyvitamin D concentrations among postmenopausal women: the Women’s Health Initiative Calcium plus Vitamin D clinical trial. Am J Clin Nutr 2010;91:1324e35. [10] Eliassen AH, Hankinson SE, Rosner B, Holmes MD, Willett WC. Physical activity and risk of breast cancer among postmenopausal women. Arch Intern Med 2010;170:1758e64. [11] Garland FC, Garland CF, Gorham ED, Young JF. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation. Prev Med 1990;19:614e22. [12] Ooi LL, Zhou H, Kalak R, Zheng Y, Conigrave AD, Seibel MJ, et al. Vitamin D deficiency promotes human breast cancer growth in a murine model of bone metastasis. Cancer Res 2010;70:1835e44. [13] Abbas S, Chang-Claude J, Linseisen J. Plasma 25hydroxyvitamin D and premenopausal breast cancer risk in a German case-control study. Int J Cancer 2009;124:250e5. [14] Despoina MJ, Brent R. Low vitamin D levels as a risk factor for cancer. BMJ 2017;359:j4952. https://doi.org/10.1136/bmj.j4952 [Accessed 31 October 2017]. [15] Dimitrakopoulou V, Tsilidis K, Haycock P, Dimou N, AlDabhani K, Martin R, et al. Circulating vitamin D concentration and risk of seven cancers: mendelian randomisation study. BMJ 2017;359:j4761. https://doi.org/10.1136/bmj.j4761 [Accessed 31 October 2017]. [16] Shao T, Klein P, Grossbarda M. Vitamin D and breast cancer. Oncologist 2012;17:36e45. [17] Haddad JG. Vitamin Desolar rays, the Milky Way, or both? N Engl J Med 1992;326:1213e5. [18] Acevedo F, Pe ´rez V, Pe ´rez-Sepu ´lveda A, Florenzano P, Artigas R, Medina L, et al. High prevalence of vitamin D deficiency in women with breast cancer: the first Chilean study. Breast 2016;29:39e43. [19] Wulaningsih W, Sagoo HK, Hamza M, Melvin J, Holmberg L, Garmo H, et al. Serum calcium and the risk of breast cancer: findings from the Swedish AMORIS study and a meta-analysis of prospective studies. Int J Mol Sci 2016;17:1487. https: //doi.org/10.3390/ijms17091487 [Accessed 16 September 2016]. [20] Wang D, Ve ´lez de la Paz OI, Zhai JX, Liu DW. Serum 25hydroxyvitamin D and breast cancer risk: a meta-analysis of prospective studies. Tumor Biol 2013;34:3509e17. [21] Welsh J. Vitamin D metabolism in mammary gland and breast cancer. Mol Cell Endocrinol 2011;347:55e60. [22] Shirazi L, Almquist M, Borgquist S, Malm J, Manjer J. Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: a nested case-control study. Breast 2016;28: 184e90. [23] Bauer SR, Hankinson SE, Bertone-Johnson ER, Ding EL. Plasma vitamin D levels, menopause, and risk of breast cancer. Doseresponse meta-analysis of prospective studies. Medicine 2013; 92:123e31. [24] Eliassen AH, Colditz GA, Rosner B, Willett WC, Hankinson SE. Adult weight change and risk of postmenopausal breast cancer. JAMA 2006;296:193e201. [25] Key TJ, Appleby PN, Reeves GK, Roddam A, Dorgan JF, Longcope C, et al. Body mass index, serum sex hormones, and breast cancer risk in postmenopausal women. J Natl Cancer Inst 2003;95:1218e26. [26] Stephenson GD, Rose DP. Breast cancer and obesity: an update. Nutr Cancer 2003;45:1e16.

Vitamin D: And its role [27] Krishnan AV, Swami S, Feldman D. Vitamin D and breast cancer: inhibition of estrogen synthesis and signaling. J Steroid Biochem Mol Biol 2010;121:343e8. [28] Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab 2011;96: 53e8. [29] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77: 204e10. [30] Holick MF. Vitamin D deficiency. N Engl J Med 2007;357: 266e81.

427 [31] Zerwekh JE. Blood biomarkers of vitamin D status. Am J Clin Nutr 2008;87:1087Se91S. [32] Khan QJ, Reddy PS, Kimler BF, Sharma P, Baxa SE, O’Dea AP, et al. Effect of vitamin D supplementation on serum 25hydroxy vitamin D levels, joint pain, and fatigue in women starting adjuvant letrozole treatment for breast cancer. Breast Cancer Res Treat 2010;119:111e8. [33] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85:6e18. [34] Jacot W, Firmin N, Roca L, Topart D, Gallet S, Durigova A, et al. Impact of a tailored oral vitamin D supplementation regimen on serum 25-hydroxyvitamin D levels in early breast cancer patients: a randomized phase III study. Ann Oncol 2016;27:1235e41.