Obesity is an established risk factor for postmenopausal
breast cancer (BCa),
insulin resistance, and
vitamin D deficiency, and all contribute to increased synthesis of mammary
estrogens, the drivers of
estrogen receptor-positive (ER+) BCa growth. As both dietary
vitamin D and
calcitriol treatments inhibit breast
estrogen synthesis and signaling, we hypothesized that
vitamin D would be especially beneficial in mitigating the adverse effects of
obesity on ER+BCa. To assess whether
obesity exerted adverse effects on BCa growth and whether
vitamin D compounds could reduce these unfavorable effects, we employed a diet-induced
obesity (DIO) model in ovariectomized C57BL/6 mice.
Breast tumor cells originally from syngeneic Mmtv-Wnt1 transgenic mice were then implanted into the mammary fat pads of lean and obese mice. DIO accelerated the initiation and progression of the mammary
tumors. Treatments with either
calcitriol or dietary
vitamin D reduced the adverse effects of
obesity causing a delay in
tumor appearance and inhibiting continued
tumor growth. Beneficial actions of treatments with
vitamin D or
calcitriol on BCa and surrounding adipose tissue included repressed Esr1,
aromatase, and Cox2 expression; decreased
tumor-derived
estrogen and
PGE2; reduced expression of
leptin receptors; and increased
adiponectin receptors. We demonstrate that
vitamin D treatments decreased
insulin resistance, reduced
leptin, and increased
adiponectin signaling and also regulated the LKB1/AMPK pathway contributing to an overall decrease in local
estrogen synthesis in the obese mice. We conclude that
calcitriol and dietary
vitamin D, acting by multiple interrelated pathways, mitigate
obesity-enhanced BCa growth in a postmenopausal setting.