Abstract 5986: WAVE2/EGF signaling and miR29 regulates WAVE2 to promote tumor growth and metastasis in triple negative breast cancer

Abstract Breast cancer is the most frequently diagnosed malignancy in women and is one of the leading causes of death due to cancer invasion, metastasis, and resistance to therapies. Among its variants, triple-negative breast cancer (TNBC) is considered the most aggressive due to its early age of diagnosis, invasive and metastatic properties with poor prognosis. TNBC is a type of breast cancer that lacks expression of the receptors that are commonly found in this type of cancer (estrogen, progesterone, and HER2), which makes it a more difficult target for treatment. Cancer invasiveness and metastasis are known to be promoted by increased cell motility and upregulation of the Wiskott-Aldrich syndrome protein (WASP) and WASP family verprolin-homologous protein (WAVE) - WAVE1, WAVE2, and WAVE3. While the contribution of WAVE2 to cancer progression is well documented, the WAVE2-mediated regulation of TNBC oncogenic properties is still under investigated. In this study, we show that WAVE2 plays a significant role in TNBC development, progression, and metastasis. To investigate this notion, we used CRISPR/Cas9 gene editing to successfully inhibit WAVE2 expression in several TNBC cell lines. In vitro, loss of WAVE2 expression inhibited 3D tumorsphere formation and invasion of TNBC cells. In vivo, in mouse models for TNBC, loss of WAVE2 inhibited tumor growth and metastasis. Mechanistically, we show that the WAVE2-mediated modulation of the oncogenic behavior of TNBC cells is in part due to its phosphorylation downstream of EGF. At the post transcriptional level, we found WAVE2 expression to be regulated by miR29. Together, our findings identify a novel post-translational WAVE2/EGF oncogenic signaling axis, along with a post-transcriptional regulatory axis downstream of miR29, which together regulate the oncogenic activity of WAVE2 in TNBC and open a new therapeutic strategy for the treatment of TNBC. Citation Format: Priyanka S. Rana, Wei Wang, Akram Alkrekshi, Vesna Markovic, Khalid Sossey-Alaoui. WAVE2/EGF signaling and miR29 regulates WAVE2 to promote tumor growth and metastasis in triple negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5986.