CCSG Pilot: Hivep2 Functions as a Immunotherapy Marker for Triple Negative Breast Cancer

Scientific Abstract Appalachia experiences higher cancer mortality rates compared to the national average, presenting a significant healthcare challenge in these regions. Our study revealed that the breast cancer mortality rate in Kentucky''s Appalachian area surpassed that of the non-Appalachian area. Triple-negative breast cancer (TNBC), characterized by the lack of ERα, PR and HER2 expression, is an aggressive disease noted for the development of recurrent, distant metastases and short survival times, particularly in young women. Most strikingly, Black women were found to have a nearly three-fold increased risk of TNBC, a risk that is also evident within the Appalachian region. The absence of effective targeted therapies and the poor response of TNBC to standard chemotherapy regimens often results in a fatal outcome. Recently, immune checkpoint inhibitors (ICIs) such as anti-PD-L1 have emerged as promising novel treatments for TNBC, offering potential improvements in patient survival. However, it is unfortunate that the majority of TNBC patients do not benefit from anti-PD-L1 or anti-PD-1 treatments. Our research indicates that Hivep2, a large zinc finger protein, is associated with a poor prognosis in breast cancer. We also observed that the loss of Hivep2 reduces the expression of PD-L1. Interestingly, we found that IFN-γ rapidly induces Hivep2 expression, which correlates with PD- L1 expression. The central hypothesis of this proposal is that Hivep2 promotes tumor immune evasion by upregulating PD-L1 in Black women and Appalachian breast cancer patients. We aim to determine whether Hivep2 protein levels in mammary glands can serve as prognostic markers for immunotherapy in breast cancer patients from Black women and the Appalachian region. Two aims are proposed to test our hypothesis. In Aim 1, we will investigate how Hivep2 promotes immune evasion by transcriptionally upregulating PD-L1 in TNBC. Aim 2 aims to evaluate the potential of utilizing Hivep2 protein levels as prognostic markers for TNBC patient immunotherapy. The Chief Information Officer (CIO) will identify a breast cancer patient advocate for our project. The patient advocate will participate in our quarterly research team meetings and provide valuable feedback. The project''s progress will be presented to the Markey Community Advisory Board, and we will collaborate with the CIO to announce the publications resulting from this project and introduce our research to the community via social media. We have assembled a strong interdisciplinary team, including Dr. Yadi Wu (MCO program), Dr. Sheng Tong (TO program), and Dr. Jinpeng Liu (Biostatistics and Bioinformatics core). We will also collaborate with the Biospecimen Procurement and Translational Pathology core and use Flow Cytometry and Immune Monitoring core facility.