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Vitamin D Identified as Possible Breast Cancer Treatment
Women who are born with BRCA1 gene mutations are at increased risk for developing breast and ovarian cancers within their lifetime, and the tumors that arise are often the triple-negative type. Although chemotherapy is the most effective treatment for triple-negative breast cancer, it has profound secondary effects.
BRCA1 is important because it is involved in repairing DNA double-strand breaks, a kind of DNA damage that is especially dangerous for the integrity of the genome (the body’s hereditary information). BRCA1 also is involved in control mechanisms during cell proliferation that make sure the DNA information has been accurately replicated and transferred to the daughter cells. Thus, BRCA1 is considered a safeguard of the genome.
Loss of BRCA1 is bad news for the information contained in a cell’s genetic blueprint. It results in genomic instability, characterized by unrepaired DNA breaks and chromosomal aberrations that compromise cell viability.
How BRCA1-mutated cells are able to form tumors has been a long-standing question. Investigators recently showed that loss of another DNA repair factor, 53BP1, allows proliferation and survival of BRCA1-deficient cells. In addition, decreased levels of 53BP1 were observed in triple-negative breast cancers, and correlated with resistance to drugs at the forefront of cancer treatment, such as poly ADP ribose polymerase (PARP) inhibitors.
The researchers identified a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1-mutated and triple-negative cancers. It turned out that loss of BRCA1 increases the expression of a protease, cathepsin L, which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, to maintain the integrity of the genome, and to proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.
The researchers also found that treatment of BRCA1-deficient tumor cells with vitamin D restores high levels of 53BP1, which results in increased genomic instability and reduced proliferation. Importantly, their evidence suggests that vitamin D treatment might restore sensitivity to PARP inhibitors in patients who become resistant. Thus, a combination of vitamin D and PARP inhibitors could represent a novel therapeutic strategy for breast cancers with poor prognosis, the researchers say.
Source: Saint Louis University; January 22, 2013.