Abstract
Abstract
Metastasis is a multistep process that leads to cancer cell dissemination and patient demise. Current technologies for identification of patients at risk for metastatic disease and the treatments for patients with distant metastases are unsatisfactory. Since metastasis is in part a motility disease, development of cell motility assays will complement current cell proliferation-based gene expression profiling assays and may improve breast cancer prognostication. The Mena family of actin binding proteins functions at the convergence of actin polymerization, directional cell movement towards EGF, and invadopodium formation pathways and plays a pivotal role in regulating cell motility. In particular, increased expression of Mena isoform, MenaINV, combined with the decreased expression of the Mena11a isoform decreases breast cancer cell cohesion and enhances cancer cell invasion and dissemination in rodent models. Tumor cells with this Mena expression pattern participate with macrophages in mouse mammary carcinoma invasion and intravasation. Intravasation sites, consisting of Mena expressing tumor cells in association with perivascular macrophages, called Tumor Microenvironment of Metastasis (TMEM), have also been found in human breast cancer and their number positively correlates with metastatic outcome in patients.
In a cohort of 100 cases of human invasive ductal carcinoma of the breast, we demonstrated that MenaINV expression levels in breast cancer cells obtained by fine needle aspiration (FNA) biopsy positively correlated with the number of TMEMs in a pre-specified field in the matching tumor tissue, while Mena11a levels showed a weak negative correlation. This suggests that MenaINV is the isoform associated with breast cancer cell invasion, intravasation and possibly metastasis in humans. The MenaINV/TMEM correlation is particularly strong in the ERPR+/Her2- cancers, implying that the MenaINV/ macrophage dependent mechanism of intravasation is particularly important in this clinical subtype. In addition, only in the ERPR+/Her2- cases, high MenaINV expression levels and TMEM scores are associated with lymph node metastasis. Furthermore, using the in vitro intravasation assay, we showed that intravasation-competent breast cancer cells obtained from patients by FNA preferentially express the MenaINV isoform. We also showed that human invasive ductal carcinomas of the breast with high MenaINV expression levels and high TMEM score express less E-cadherin, which may render these cells less cohesive and thus more motile and prone to invasion, intravasation, and metastasis.
Our data indicate that MenaINV is the isoform of Mena associated with cell discohesion, intravasation competency and potentially metastatic outcome in human breast carcinoma. Thus, MenaINV has the potential to become both a prognostic marker and a target for therapy.
Citation Format: Maja Oktay, Sumanta Goswami, Minna Roh-Johnson, Sara Maleki, Shannon Hughes-Alford, Thomas Rohan, Frank Gertler, Joan Jones, John Condeelis. MenaINV expression is associated with discohesion, intravasation and possibly metastasis in human invasive ductal carcinoma of the breast. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-274. doi:10.1158/1538-7445.AM2013-LB-274