CHSU Discovery

Abstract

Breast Cancer, the most common type of cancer in women, is the second leading cause of cancer deaths in women. Furthermore, 1 in 8 women, about 12%, will develop invasive breast cancer over the course of her lifetime. In the case of Triple Negative Breast Cancer (TNBC), the three most common receptor variants to promulgate most breast cancer growth- estrogen, progesterone, and HER-2- are not present. TNBC has a dismal prognosis compared to other breast cancer subtypes. Additionally, BRCA mutations are associated with an increased risk for developing breast cancer and occurs more frequently in Triple Negative Breast Cancer (TNBC). Cancer patients with BRCA mutations are commonly treated with PARP inhibitors, as the cells become reliant on the PARP enzyme to repair the damaged DNA that was once repaired by the functional BRCA gene. Interestingly, combination therapy with the DNMT inhibitor guadecitabine and the PARP inhibitor talazoparib enhanced PARP efficacy in BRCA-mutant and BRCA normal breast cancer cells. Still, however, breast cancer patients develop resistance to PARP inhibitors, and the molecular mechanisms are unknown. Our lab previously observed evidence of increased activity of the stress response transcription factor heat shock factor 1 (HSF1) in response to PARP inhibitors, but its role in the killing efficacy of PARP inhibitors remains unknown. To analyze the heat shock factor response to talazoparib exposure, cell viability assays and western blotting were conducted. Using HCC 1395 and HCC 1937 breast cancer cells, with both lines being BRCA mutants, we observed the IC50, dose at which 50% of cells are alive after treatment, of talazoparib, a PARP inhibitor in clinical trials for breast cancer, to be approximately 90 nM in HCC 1395 and 21 uM in HCC 1937 cells. Interestingly, the HCC 1395 cells were found to have significantly lower protein levels and protein activity of HSF1 compared to HCC 1937 cells. Additionally, treatment of HCC1395 cells with talazoparib led to increased activation of HSF1. Lastly, in HCC 1395 cells, which have low HSF1 levels and activity, a significant increase in the IC50 was observed when HSF1 was exogenously expressed. Taken together, these data strongly suggest that HSF1 is activated in response to PARP inhibition, and HSF1 can mitigate the effectiveness of PARP inhibitors. These results may indicate that HSF1 can potentially contribute to PARP inhibitor resistance. For future directions, we aim to assess whether DNMT inhibition can enhance the response of PARP inhibitors in the context of high HSF1 activity.