Abstract 341: Breast cancer cell adhesion and degradome interact to drive metastasis

Abstract

Abstract Although primary breast tumors are detected early in most cases, it is inevitable that many patients remain at risk for future recurrence and death due to micrometastases. We investigated the metastatic process with a focus on matrix metalloproteases (MMPs) within the degradome and on integrins and E-cadherin within the adhesome. We have performed comparative studies with a set of non-metastatic (BT-474, T47D, MCF7) versus metastatic (MDA-MB-231, SUM149, SUM159) human breast cancer cell lines and xenografts. Experiments were performed to measure growth rate, migration, invasion, and colony formation. Immunoblotting and immunohistochemistry revealed a higher expression of MMPs and heterophilic cell adhesion molecules integrin β1 and lower expression of homophilic cell adhesion molecule E-cadherin in the metastatic tumor cells and xenografts. Using zymography and activatable fluorescent probes for noninvasive imaging of MMPs, we demonstrated that metastatic breast cancer cells and tumors displayed an elevated degradome activity as compared to non-metastatic cells and tumors. Cell adhesion and cell aggregation assays showed an increased heterophilic and decreased homophilic adhesion in the metastatic models. Inhibiting MMPs reduced the expression of integrin β1, and stimulating integrin β1 resulted in higher MMP activities in metastatic cells. Re-expression of E-cadherin in metastatic cells led to a reduced expression of active integrin β1. Finally, circulating breast cancer cells and cells from lung metastatic nodules generated from metastatic tdTomato-fluorescing breast cancer cells displayed a reduced expression of active integrin β1 and less epithelial-mesenchymal-transition (EMT) marker protein S100A4. Our results indicate that proteolytic ECM remodeling by MMPs and cell adhesion by integrin β1 and E-cadherin are interdependent processes that control transformation from benign to invasive carcinoma and are critical for metastasis. Citation Format: Asif Rizwan, Menglin Cheng, Zaver M. Bhujwalla, Balaji Krishnamachary, Lu Jiang, Kristine Glunde. Breast cancer cell adhesion and degradome interact to drive metastasis. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 341. doi:10.1158/1538-7445.AM2015-341