Principal Investigator: Song Yao, PhD, Roswell Park Cancer Institute, Buffalo

Low levels of vitamin D are thought to be linked to increased risk of breast cancer, particularly the triple-negative (TN) subtype. With TN breast cancer, cells test negative for estrogen receptors (ER-), progesterone receptors (PR-), and the HER2 (HER2-) gene, making the cancer unresponsive to the currently available hormonal or HER2 targeted treatments.  African American (AA) women typically have significantly lower levels of vitamin D than their European American (EA) counterparts, potentially accounting for the strikingly high incidence of TN breast cancer among this group. This study observed the associations between the level of vitamin D and the TN status of the patients, and also examined single nucleotide polymorphisms (SNPs) in the vitamin D receptor (VDR) gene. SNPs are genetic variations in a single DNA molecule that can have a major impact on risk of diseases and response to treatments.

Women with breast cancer showed lower levels of vitamin D than women without cancer (22.8 versus 26.2 ng/mL), and those with TN breast cancer before menopause had the lowest levels (17.5 ng/mL). For each 10 ng/mL increase in vitamin D, there was a 64 percent reduction in the risk of having TN breast cancer. The prevalence of severe vitamin D deficiency (< 10 ng/mL) was almost six times higher in African American women than that in European American women (34.3 percent vs 5.9 percent). Two SNPs were found to explain, in part, the higher risk of ER-negative breast cancer in AA women.

"Our results indicate that blood levels of vitamin D are inversely linked with the risk of breast cancer, particularly TN type, which is more common in African American women and is known to have poorer prognosis." said Dr. Song Yao of Roswell Park Cancer Institute. "To our knowledge, this is the first study to indicate that vitamin D and related genetic variants may account, in part, for breast cancer racial disparities. Future work is warranted to investigate whether these disparities can be mitigated, to some extent, by maintaining sufficient levels of vitamin D."

Identification of Genes Required to Suppress Tumor Transformation in Triple Negative Breast Cancer

Principal Investigator: Stephen Elledge, PhD, Brigham and Women's Hospital

Subtypes of breast cancer are generally diagnosed based on the presence or absence of three receptors that play important roles in breast cancer - estrogen receptors, progesterone receptors, and human epidermal growth factor receptors. The triple-negative (TN) subtype is characterized by the absence of all three of these receptors and does not respond to current targeted breast cancer therapies. African American women are at a greater risk of developing TN breast cancer than less aggressive subtypes of breast cancer. Dr. Stephen Elledge and colleagues recently identified a gene, PTPN12 tyrosine phosphatase, as a tumor suppressor in women with TN breast cancer. PTPN12 suppresses the growth and transformation of mammary epithelial cells in breast tissue, and is frequently compromised in TN breast cancer. Restoring PTPN12 function in deficient TN breast cancer cells can block their ability to form tumors and become metastatic. This effect is also seen in cells with inhibition of PTPN12-regulated tyrosine kinases thus suggesting that TN breast cancer cells are dependent on proto-oncogenic tyrosine kinases constrained by PTPN12.

"Our data suggests that PTPN12 is commonly inactivated in triple-negative breast cancer and results in activation of cellular tyrosine kinases which could be targets for this intractable cancer," said Dr. Elledge. "While we are still understanding the triple-negative subtype, our research findings could play a key role in improving the treatment of this disease."

Source: US Department of Defense Congressionally Directed Medical Research Programs