A research team has discovered a molecular pathway that contributes to triple-negative breast cancer, an often deadly and treatment resistant form of cancer that tends to strike younger women.
The team led by Susana Gonzalo, Ph.D., assistant professor of biochemistry and molecular biology at Saint Louis University, also identified vitamin D and some protease inhibitors as possible new therapies and discovered a set of three biomarkers that can help to identify patients who could benefit from the treatment.
In the recent breakthrough, Gonzalo’s lab identified one pathway that is activated in breast cancers with the poorest prognosis, such as those classified as triple-negative. These cancers often strike younger women and are harder to treat than any other type of breast cancer.
Experiments performed in Gonzalo''s laboratory, in collaboration with the laboratories of Xavier Matias-Guiu and Adriana Duso (IRBLleida, Spain), showed that activation of this novel pathway not only allows tumor cells to grow unchecked, but also explains the reduced sensitivity of these types of tumors to current therapeutic strategies.
Importantly, vitamin D plays a role in turning off this pathway, providing a safe and cost-effective strategy to fight these types of tumors.
BRCA1 is a well-established tumor suppressor gene. Women who carry mutations in this gene have a high risk of developing breast and ovarian cancer. Tumors that arise often lack expression of three receptors: estrogen, progesterone and HER2 (thus, “triple-negative”), and do not respond to hormone therapy.
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 PARP inhibitors.
Gonzalo’s team has found a pathway responsible for the loss of 53BP1 in breast cancers with poor prognosis, specifically BRCA1 mutated and triple-negative. It turns out that loss of BRCA1 increases the expression of a protease, known as cathepsin L (CTSL), which causes the degradation of 53BP1. Cells that have lost both BRCA1 and 53BP1 have the ability to repair DNA, maintain the integrity of the genome, and proliferate. Thus, the protease helps cells with faulty BRCA1 to survive.
If lowering the levels of 53BP1 allows BRCA1 deficient cells to thrive and do their worst, increasing the levels of the protein offers a promising strategy for treatment of breast tumors.
In previous research, Gonzalo’s team showed that vitamin D inhibits CTSL-mediated degradation of 53BP1 in non-tumor cells, as efficiently as specific CTSL inhibitors. This time, they 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 the 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.
In a final exceptionally useful discovery, Gonzalo and collaborators found that high levels of nuclear CTSL and low levels of 53BP1 and nuclear vitamin D receptor (VDR) are a clear marker that identifies certain triple-negative breast cancer patients, biomarkers that offer the potential to customize future breast cancer therapies.
In particular, this triple-biomarker signature will allow the identification of patients in whom the pathway is on and who might benefit the most from vitamin D treatment.
The research was published recently in The Journal of Cell Biology.