Regulation of apoptosis in adipocytes and breast cancer cells by 1,25-dihydroxyvitamin D₃: a link between obesity and breast cancer

Abstract

Modulation of apoptosis is emerging as a promising strategy for prevention and treatment of breast cancer and obesity because removal of mammary cancer cells and mature adipocytes through this process will result in decreasing tumor size and produce long-term reduction in adipose tissue mass. The hormone 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) triggers apoptosis in breast cancer cells and adipocytes via the induction of the apoptotic Ca2+ signal - a sustained increase in concentration of intracellular Ca2+. This signal acts as an apoptotic initiator that directly recruits Ca2+-dependent apoptotic effectors, calpain and caspase 12, in breast cancer cells and adipocytes. Normal mammary epithelial cells are resistant to 1,25(OH)2D3-induced, Ca2+-mediated apoptosis because the mechanisms regulating Ca2+ in these cells do not sustain Ca2+ increase at the apoptosis-inducing level. Induction of apoptosis with 1,25(OH)2D3 in adipose tissue, particularly in the tumor-surrounding adipose tissue involved in tumor progression, can contribute to the anticancer effects of the hormone. The 1,25(OH)2D3-Ca2+ link between obesity and breast cancer supports the rationale to include Ca2+-dependent apoptotic proteases as molecular targets for the discovery of new therapeutic and preventive agents for breast cancer and obesity; it also supports the recommendation to maintain adequate or increased vitamin D and calcium intakes as one of the possible ways to protect against breast cancer and decrease adiposity.

Vitamin D-mediated apoptosis in cancer and obesity

“…Vitamin D (vitamin D 3 ) is a precursor of the secosteroid hormone 1,25-dihydroxyvitamin D 3 (1,25(OH) 2 D 3 ), which functions via the relatively well-defined genomic and nongenomic mechanisms in a number of cell types, tissues, and organs [1][2][3][4]. Moreover, paracrine and autocrine modes of action of 1,25(OH) 2 D 3 appear to be of importance in some cells [1,2].…”

“…Vitamin D deficiency/insufficiency has been associated with the increased risk of colorectal, breast, ovarian, prostate, pancreatic, skin, and other types of cancer as well as obesity; however, causality in these associations remains unproven [4,6,[11][12][13][14][15][16][17][18][19][20]. A promising approach for the prevention and treatment of cancer and obesity is targeted, differential induction of apoptosis resulting in elimination of tumor cancer cells and reduction of the number of fat cells in adipose tissue [6-8, 11, 13, 20].…”

“…Cancer and obesity can be considered as interrelated diseases [3,4,6,11]. Epidemiological studies have shown that obesity is a significant risk factor for several cancers [6,12,21], but, again, mechanisms linking obesity and cancer are not well understood.…”

“…Epidemiological studies have shown that obesity is a significant risk factor for several cancers [6,12,21], but, again, mechanisms linking obesity and cancer are not well understood. Cancer and obesity can arise as a consequence of dysregulation of common endocrine, paracrine, and intracellular signaling pathways determining the fate of both cancer cells and adipocytes [4,6,11,21]. Obesity appears to increase risk of cancer via multiple mechanisms regulating proliferation, differentiation, apoptosis, inflammation, and cell signaling mediated by obesity-related hormones [including 1,25(OH) 2 D 3 ] and growth factors known to favor cancer cell promotion, progression, and tumor growth [3,6,11,21].…”

“…Obesity appears to increase risk of cancer via multiple mechanisms regulating proliferation, differentiation, apoptosis, inflammation, and cell signaling mediated by obesity-related hormones [including 1,25(OH) 2 D 3 ] and growth factors known to favor cancer cell promotion, progression, and tumor growth [3,6,11,21]. On the other hand, risk factors for the development of cancer and obesity are determinants of vitamin D status [3,4].…”