A molecular investigation of vitamin D deficiency in breast cancer [electronic resource]

Vitamin D is the precursor to the potent steroid hormone 1α, 25-dihydroxyvitamin D3 (calcitriol). Calcitriol binds to the vitamin D receptor (VDR) and regulates gene transcription by binding to vitamin D response elements in target genes. VDR belongs to the superfamily of steroid/nuclear hormone receptors, and functions similarly to other known steroid hormones like estrogen (through Estrogen Receptor α and β) and progesterone (through the Progesterone Receptor) in humans. Given the structural similarity and functional impact of vitamin D signaling, serum levels of vitamin D are an important consideration in human health. Specifically, vitamin D deficiency is proven to accelerate the progression of multiple diseases, including diabetes mellitus, multiple sclerosis, and breast cancer. Breast cancer patients frequently have pre-existing vitamin D deficiency when their cancer develops. Several epidemiological studies show an inverse association between breast cancer risk and vitamin D status in humans, although some studies have failed to find an association. Studies examining the connection between serum 25(OH)D levels and prognostic indicators of breast cancer report that patients with vitamin D deficiency [low serum 25(OH)D] have a more aggressive molecular phenotype of breast cancer and worse prognostic indicators. However, it remained unclear whether the association between low vitamin D levels and prognosis was mechanistically causative. Further, the impact of systemic vs. tumor specific effects of the active hormone had yet to be explored in a conclusive manner in breast cancer. Here I demonstrate that vitamin D deficiency causes both a systemic and tumor autonomous enhancement in the progression of breast cancer using a combination of data from cell culture, animal models, and a recently completed clinical trial. In the context of tumor initiating cells (TICs), functional VDR signaling inhibits the capacity of these cells to self-renew, which is mediated in part through Wnt signaling. In the setting of obesity (a known risk factor for aggressive breast cancer), vitamin D counteracts the deleterious effects of inflammation and insulin signaling. Further, we discovered that vitamin D signaling directly inhibits expression of the metastasis promoting gene ID1, and this is an essential pathway for the restriction of tumor growth by vitamin D signaling. In this setting, loss of functional VDR signaling in a tumor autonomous manner can independently accelerate progression in vivo. Finally, we demonstrate that these findings are relevant in humans with their vitamin D status predicting the level of ID1 expression in their tumors. Our results indicate that avoiding vitamin D deficiency could result in improved prognosis for breast cancer patients. Overall, the work within this thesis highlights the need to carefully monitor vitamin D status in breast cancer patients. The molecular mechanisms clarified within this body of work support the hypothesis that vitamin D deficiency is mechanistically causative in driving multiple aspects of tumor progression. As a follow up to this work in the future, therapeutic strategies targeting ID1 using vitamin D as a probe could be investigated for specific use in delaying disease progression in breast cancer patients. Further, more robust clinical trial data on the prognostic effects of correcting vitamin D deficiency would serve as further evidence for incorporating this risk factor into the standard of care in treating breast cancer.

Advisor: Feldman Brian (Brian Jay)
Cyert Martha S.
Giaccia Amato J.
Peehl Donna
Winslow Monte advisor. Thesis advisor