Abstract 1324: EphA2 Expression in Breast Cancer Mediates Osteoclast Expansion and Promotes Osteolytic Bone Metastasis

Abstract

Breast cancer is the most diagnosed cancer in the U.S., with a 5-year survival rate of less than 30% for patients with distant metastases. Bone metastases are present in over 70% of metastatic breast cancer patients, and current treatments treat the symptoms of osteolytic bone metastasis (OBM), but do not improve survival rates. OBM is characterized by an increase in osteoclast proliferation and bone-resorbing activity. Moreover, receptor tyrosine kinase, Ephrin-type-A 2 receptor (EphA2), is highly expressed in bone metastases, and previous evidence suggests its involvement in OBM and anti-tumor immunity. EphA2 participates in both forward and reverse signaling during receptor/ligand engagement and mediates various biological processes such as tissue organization and homeostasis and inflammation, as well as oncogenic processes like epithelial-mesenchymal transition. However, the mechanism by which EphA2 mediates the expansion of osteoclasts is not well understood. Analysis of transcriptomic data of patients with bone metastases in The Metastatic Breast Cancer Project (Provisional, December 2021) resulted in over 3500 genes that significantly correlated with EphA2 expression (Spearman's Correlation ≥ 0.35). Using a publicly available Gene Ontology reference list for myeloid differentiation, we identified 155 genes that have a significant positive correlation with EphA2 expression. To assess the effect of EphA2 expression on genes associated with osteoclasts, we compared the same samples to reference lists for osteoclast differentiation and proliferation. We identified 17 genes of interest that significantly correlate with EphA2 expression, further underscoring the possible involvement of EphA2 in OBM. We then compared the patients without bone metastases to the same osteoclast reference lists and found no significant correlations. We hypothesize that increased expression of EphA2 in breast cancer cells at the site of bone metastasis promotes osteoclast expansion, leading to OBM. We aim to investigate EphA2 reverse signaling in myeloid progenitor cells, osteoclasts, and bone metastasis-associated macrophages. We will utilize breast cancer mouse models to elucidate the effects of EphA2 inhibition on immune cell populations, bone metastasis, and tumor progression. We aim to reduce OBM and tumor burden by reducing the expansion of osteoclasts and shifting the immune cells to an anti-tumorigenic phenotype, which will offer new treatment strategies for osteolytic breast cancer. Citation Format: Dominique Parker, Verra Ngwa, Logan Northcutt, Natalie Bennett, Erik Beadle, Jade Miller, JIn Chen, Julie Rhoades. EphA2 Expression in Breast Cancer Mediates Osteoclast Expansion and Promotes Osteolytic Bone Metastasis [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 1324.