Abstract 4942: Heme targeting and its mechanistic role in triple-negative breast cancer suppression

Abstract

Abstract Breast cancer is the second leading cause of cancer-related deaths and comprises of approximately 30% of all cancer cases affecting women in the United States. There are three subtypes of breast cancer based on receptor profiles, with the third subtype being triple-negative breast cancer. TNBC accounts for about 10-15% of all breast cancers. The TNBC subtype lacks estrogen, progesterone, and HER2 receptors; it is associated with BRCA1 and BRCA2 mutations. This type of cancer has poor prognosis, tends to be more aggressive, and has limited treatment options compared to the other two subtypes. Heme is an essential molecule in the oxidative phosphorylation pathway and in the generation of reactive oxygen species (ROS). ROS generation causes oxidative stress and induces DNA damage in breast cancer. Therefore, targeting its activity potentially suppresses TNBC tumors. Heme-sequestering protein 2 (HeSP2) binds and sequesters heme. It has been shown that HeSP2 treatment of MDA-MB-231 cells inhibited cell proliferation and colony formation. Moreover, HeSP2 suppresses tumor growth in subcutaneously implanted TNBC MDA-MB-231 xenografts in NOD/SCID mice. Furthermore, in vitro studies using murine TNBC cell models 4T1-fluc Neo and EMT6-fluc Puro cells have also shown that cell proliferation and colony formation were inhibited after HeSP2 treatments of increasing concentrations. Thus, these results encourage the potential use of HeSP2 for breast tumor suppression. To further explore the effects of heme targeting and sequestration, we will determine heme flux in TNBC cell models by measuring the levels of heme uptake, export, synthesis, and degradation. Moreover, we will examine mitochondrial markers for OXPHOS complexes in HeSP2 treated TNBC xenografts using immunohistochemical analysis. Further studies are still underway to understand the role of heme in breast cancer, with preliminary results indicating that heme targeting, and sequestration effectively suppress triple-negative breast cancer and its progression. Citation Format: Eranda Berisha, Maria del Carmen Chacon Castro, Adnin Ashrafi, Narges Salamat, Parinaz Sadat Alemi, Li Zhang. Heme targeting and its mechanistic role in triple-negative breast cancer suppression. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4942.