PARP Enzyme Family and Breast Cancer

In recent years, PARP-inhibiting drugs have received significant attention as potential cancer therapies. The first PARP inhibitor was approved by U.S. Food and Drug Administration in 2014 for certain ovarian cancers, and about 140 clinical trials – including several at UT Southwestern – are currently examining the impact of these drugs on different types of cancer.

Using patented technology we developed at UT Southwestern, we identified very different PARP1 signatures in various breast cancer subtypes. The signatures, which are compared to bar codes at the grocery store, reveal how proteins from breast cancer subtypes are modified differently by the enzyme PARP1, which stands for poly (ADP-ribose) polymerase 1. This enzyme is critical to the cancer cell’s DNA repair response to chemotherapy that damages DNA, the cell’s genetic material. PARP1 is the major target for PARP1 inhibitor drugs, the first three of which were recently approved by the Food and Drug Administration to treat ovarian cancer. PARPs also play a key role in inflammatory and cardiovascular diseases, and there is strong evidence from animal models that links PARP inhibitors to improved outcomes in both types of diseases. 

PARP1 inhibitors are also being evaluated against other types of cancer in clinical studies at UT Southwestern and at dozens of other medical centers around the world.  The drugs target cancer cells by blocking the function of PARP1 and crippling DNA repair. Although DNA damage is recognized as a potent activator of the PARP1 response, the cell-signaling cascades that follow PARP1 activation are poorly understood in other contexts. 

The UT Southwestern researchers found significant differences between the signatures of noncancerous breast tissue cells that contained working copies of the tumor-suppressing BRCA1 and BRCA2 genes and breast cancer cells that lacked working BRCA1 and BRCA2 genes. Mutations in those two genes are thought to account for an estimated 10 percent of all breast cancer cases.