MTA2 is a metastasis promoter in breast cancer cells.
Authors: KR Covington, I Barone, Y Cui, A Tsimelzon, A Rodriguez, T Wang, SA Fuqua
Journal: Cancer Research (2009)

Abstract Abstract #2047 Background: Breast cancer mortality is often the result of distant metastasis. It is believed that epigenetic regulation of gene expression plays an important roles in cancer biology. We have previously shown that metastasis tumor associated (MTA)2 is a repressor of estrogen signaling in estrogen receptor (ER) α-positive breast cancer cells and that overexpression of MTA2 rendered ERα-positive cells resistant to the effects of antiestrogens, such as tamoxifen. Knockdown of Rho GDP dissociation inhibitor (Rho GDIα), an inhibitor of the Rho family, conferred resistance to tamoxifen concomitant with MTA2 upregulation in ERα-positive cells. Furthermore, we found, using a retrospective cohort, that patients with high MTA2 and low Rho GDIα expression had poorer recurrence-free survival after tamoxifen treatment. Thus, MTA2 overexpression is associated with an aggressive, hormone-independent phenotype. We therefore hypothesize that MTA2 might similarly enhance the aggressiveness of ERα-negative breast cancer cells, and explored molecular mechanisms of metastasis.&amp;#x2028; Materials and Methods: We compared the invasive and migratory phenotype of MDA-MB-231 cells stably overexpressing either MTA2 or empty vector using modified Boyden chamber invasion, wound healing, and soft agar colony formation assays. Immunoblot assay was used to assess changes in protein expression. MDA-MB-231 cells overexpressing MTA2 or vector were injected into the number four mammary gland as tumor xenografts in female athymic nude mice to test for changes in metastatic potential in vivo. Differential gene expression between the MTA2-overexpressing and vector control MDA-MB-231 cells was determined using Affymetrix microarray technology.&amp;#x2028; Results: Stable MDA-MB-231 transfectants overexpressing MTA2 were generated. MTA2-overexpressing cells exhibited more cell to cell contacts, and fewer spindle-shaped cells than vector control. MTA2-overexpressing cells were approximately three times more invasive than vector control, and exhibited increased ability to form colonies in soft agar. However, they were less motile in wound healing assays. As xenografts, MTA2 stably transfected cells rapidly metastasized to the lung, lymph nodes, and skin. Metastases were not observed with vector control cells during the course of the experiment. Using microarray analysis, we identified enriched ontologies for a number of relevant pathways, including Rho signaling and cell adhesion. We have validated that MTA2-overexpressing cells have reduced expression of Rho GDIα, and we are exploring the role of Rho signaling as an effector of MTA2's impact on metastasis.&amp;#x2028; Conclusion: MTA2 overexpression significantly alters the morphology and metastatic behavior of ERα-negative breast cancer cells. We hypothesize that MTA2 regulates pathways regulating cell adhesion, migration, and the Rho signaling pathway, thus increasing the metastatic ability of MTA2-overexpressing cells. In other models, MTA2's activity relies on its associated histone deacetylase activity, thus HDAC inhibitors may be able to block the effects of MTA2 overexpression, making MTA2 a potential therapeutic target. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2047.