A deficiency in vitamin D is associated with tumor progression and metastasis in breast cancer, suggests a new study.
The study, primarily conducted using cell lines and mice, also identified an association between vitamin D levels and the expression of ID1, an oncogene that has been associated with tumor growth and metastasis in breast cancer and other cancer types.
The study findings were published on March 2 in Endocrinology.
Vitamin D, which is obtained from food and supplements or produced by the body in response to sun exposure, is converted into the hormone calcitriol in several different body tissues, including breast tissue. Calcitriol, in turn, binds to the vitamin D receptor (VDR), which regulates a large number of genes, some of which are associated with cancer.
“A number of large studies have looked for an association between vitamin D levels and cancer outcomes, and the findings have been mixed,” said Brian J. Feldman, M.D., Ph.D., of the Stanford University School of Medicine. “Our study identifies how low levels of vitamin D circulating in the blood may play a mechanistic role in promoting breast cancer growth and metastasis.”
Dr. Feldman and his colleagues studied vitamin D deficiency in mouse models of human breast cancer and in breast cancer cell lines.
They found that mice injected with tumor cells and fed a diet low in vitamin D developed tumors more quickly, and developed larger tumors, than mice fed a standard diet. In separate experiments, they found that a breast cancer cell line that produces highly aggressive, metastatic disease in mice had low levels of VDR expression, whereas a cell line that does not lead to metastases when introduced into mice had normal levels.
Additional experiments—involving tumors formed in mice from breast cancer cells that the research team manipulated to affect VDR expression—showed that in more than half of the mice whose tumors had low levels of VDR expression, the tumors spread to the liver. None of the mice with tumor cells that had normal VDR expression had evidence of metastatic disease.
“Our results indicate that loss of vitamin D/VDR signaling is sufficient to convert the cells from nonmetastatic to metastatic,” they wrote.
Further analyses of tumors in the mice treated with standard or vitamin D-deficient diets singled out the ID1 gene—high expression of which has been linked with breast cancer metastasis. The gene was more highly expressed in tumors from vitamin D-deficient mice, they found, as well as in breast cancer cells engineered to have low VDR expression.
Additional work suggested that the vitamin D receptor regulates the ID1 gene and identified the section of the ID1 gene that VDR signaling may act on.
The investigators then wanted to determine whether their findings applied to breast cancer in humans. In a widely studied human breast cancer cell line, they showed that treating the cells with calcitriol reduced expression of the ID1 protein. And when they analyzed vitamin D and ID1 expression in tumors from a small clinical trial of women with early-stage breast cancer, they found that higher levels of circulating vitamin D were associated with lower levels of ID1 expression in tumors. [The trial was stopped early so there is no data on patient outcomes.]
Stanley Lipkowitz, M.D., Ph.D., chief of the Women’s Malignancies Branch in NCI’s Center for Cancer Research, said the study’s findings were “provocative,” but that there are still important questions to answer. Further work is needed, he said, to more definitively show that the findings are generalizable to humans and, if so, whether they only apply to specific types of breast cancer.
More research is also needed to extend the study’s findings, Dr. Lipkowitz continued. For example, the study did not address whether correcting a vitamin D deficiency could be beneficial to outcomes in women with breast cancer, he said.
The findings from this study aside, maintaining normal levels of vitamin D is important for women with breast cancer, Dr. Feldman stressed.
“Women over 60 are at increased risk for osteoporosis and the therapies used to treat breast cancer make this risk even greater,” he said. “Having normal vitamin D levels is especially important for women with breast cancer to optimize bone heath independent from the potential effects on the tumor we identified.”
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