Advisory Committee Chair
Eddy S Yang
Advisory Committee Members
Robert Van Waardenburg
Susan Nozell
Donald Buchsbaum
Rajeev Samant
Document Type
Dissertation
Date of Award
2016
Degree Name by School
Doctor of Philosophy (PhD) Heersink School of Medicine
Abstract
We previously reported that HER2+ breast cancers are susceptible to Poly (ADP-Ribose) polymerase inhibitors (PARPi) alone, agents that are efficacious against homologous recombination (HR) deficient tumors. However, this phenomenon was determined to be independent of a HR repair deficiency but rather due to suppression of NF-κB activity and signaling by PARP inhibition. Further, HER2 overexpression itself was necessary and sufficient to confer this susceptibility. Interestingly, PARP1 and phosphorylated RelA/p65 (NF-κB) levels were found to be elevated in human HER2+ breast cancers compared to luminal breast cancers. These data suggest a possible interplay between HER2, PARP1, and NF-κB, and how this interplay influences PARPi sensitivity is the main goal of this dissertation. We hypothesize that the elevated PARP1 protein levels observed in HER2+ breast tumors are regulated at the post-transcriptional level via a microRNA. Due to the fact, that resistance to HER2 agents may activate compensatory mechanisms to maintain downstream signaling we predict HER2+ trastuzumab resistant (TR) breast cancer cells will retain sensitivity to PARPi. Our data indicates that HER2+ breast tumors with high PARP-1 protein levels expressed lower levels of let-7a. We also discovered that PARP1’s was regulated at the post-transcriptional level by the let-7a microRNA in HER2+ breast cancer cells. It was also observed that both pharmacological and genetic inhibition of PARP1 decreased NF-κB activity. Specifically, we observed that suppression of PARP1 levels reduced binding of the p65 transcription factor to the promoter of a NF-κB target gene, interleukin 8 (IL-8). Finally, we detected that HER2+ trastuzumab resistant breast cancer cells remained sensitive to PARPi. In conclusion, our data suggest that an interplay between the HER2, PARP1, and NF-κB signaling pathways exists which may be a determinant behind PARPi susceptibility in HER2+ breast cancer cells. Ultimately, the data from these studies will lead to better understanding of PARP biology and broaden the use of PARPi in the clinic.
Recommended Citation
Wielgos, Monicka Ewa, "Interplay Between Her2, Parp1, And Nf-Κb In Breast Cancer: Potential Therapeutic Implications" (2016). All ETDs from UAB. 3323.
https://digitalcommons.library.uab.edu/etd-collection/3323