Abstract 203: Promotion of metastasis of ERBB2-positive breast cancer by mesenchymal stem cells via exosomes-mediated activation of ERBB2/ERBB3→PI3K/Akt singaling pathway

Abstract Elevated expression of ERBB3 receptor correlates with increased distant metastasis of breast cancers with amplification and/or overexpression of ERBB2 (HER2/neu), which the underlying molecular mechanism remains unclear. In recent years, cumulative studies have demonstrated that mesenchymal stem cells (MSCs), one of the important cellular components in tumor microenvironment, play important roles in multiple hallmarks of cancer including invasion and metastasis. However, its role in metastasis of ERBB2-positive breast cancer as well as the precise mechanisms are largely unrevealed. In our current study, we found that co-culture with MSCs or treatment with exosomes derived from MSCs can significantly promote the epithelial-mesenchymal transition (EMT), migration and invasion of ERBB2-positive breast cancer cells. MSCs exhibited significantly higher expression of NRG-1, a known ligand of ERBB3, as compared with ERBB2-positive breast cancer cells. The presence of NRG-1 in exosomes derived from MSCs was also evidenced. Mechanistically, co-culture with MSCs or treatment with exosomes derived from MSCs induced upregulation of ZEB1 and Slug via activation of downstream PI3K/Akt singaling to promote EMT of ERBB2-positive breast cancer cells. In addition, the expression of MMP2 was also upregulated by treatment with MSCs-derived exosomes, which enhanced the migration and invasion of ERBB2-positive breast cancer cells simultaneously. Interestingly, our study further demonstrated that treatment with MSCs-derived exosomes could significantly downregulate the expression of PTEN, the key negative regulator of PI3K/Akt singaling, via transferring three PTEN-targeting miRNAs (miR-21-5p, miR-23a-3p, and miR-148a-3p). Taken together, we presented here that MSCs may, on the one hand, directly activate the ERBB2/ERBB3→PI3K/Akt signaling pathway in ERBB2-positive breast cancer cells through the expression and secretion of NRG-1 via exosomes. Meanwhile, miR-21-5p, miR-23a-3p, and miR-148a-3p targeted delivery by exosomes specifically downregulated the expression of PETN, thus reliefs the negative regulation of PI3K/Akt signaling in ERBB2-positive breast cancer cells. These effects of MSCs act in concert to promote the metastasis of ERBB2-positive breast cancer. Our study lays a theoretical foundation and preliminary experimental basis for the development of novel combined therapies for patient with ERBB2-positive breast cancer through co-targeting MSC-derived NRG-1 and miR-21-5p, miR23a-3p, miR148a-3p/PTEN axis in tumor microenvironment in the future. Citation Format: Yating Wu, Li Chen, Yue Cao, Qinfeng Huang, Huimin Niu, Xiaofeng Lai, Meng Zhao, Huihui Yan, Hui Lyu, Bolin Liu, Shenghang Zhang, Shuiliang Wang. Promotion of metastasis of ERBB2-positive breast cancer by mesenchymal stem cells via exosomes-mediated activation of ERBB2/ERBB3→PI3K/Akt singaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 203.