Abstract 1403: Inhibiting the Rho pathway in the triple-negative, basal-like breast cancer cell line, TMX2-28, inhibits invasive behavior

Abstract

Abstract Breast cancer is a heterogeneous disease that varies in its biology and response to therapy. It ranks among the top four most common cancers and comprises about 23% of female cancers. A foremost threat to patients is tumor invasion and metastasis, with the greatest risk to patients diagnosed with triple-negative (TN) and/or basal-like breast cancers. To manifest their malignant potential, tumor cells must have the ability to invade the extracellular matrix (ECM), enter organ systems, travel to and invade distant tissues, and establish new tumor sites. Degradation of the ECM requires the use of proteolytic enzymes such as matrix metalloproteinases (MMPs). Proteins that control cell-cell and ECM interactions (Rho proteins) are also thought to play a role in invasion and metastasis in a proteolytic-independent way, by controlling cell morphology, motility, and interactions with the tumor microenvironment. With 90% of cancer deaths resulting from metastasis, a greater understanding of the molecular mechanisms underlying cancer cell spreading is needed. Identification of factors that influence these processes could result in the development of effective therapies against invasive breast cancers. To identify new therapeutic targets for TN and basal-like breast cancers we are using a tamoxifen-selected derivative of the MCF-7 breast cancer cell line: TMX2-28. In contrast to MCF-7, TMX2-28 are TN in their hormone receptor expression, have an altered gene expression profile that includes luminal and basal cytokeratins, and display aggressive growth as evidenced by reduced doubling time, prolonged S-phase and invasive properties. Despite their aggressive phenotype, TMX2-28 retains a morphology similar to non-aggressive MCF-7 cells, suggesting that their invasion may be proteolytic-independent. Since previous studies have shown that some TN and basal-like breast cancers utilize a proteolytic-independent invasion mechanism, TMX2-28 may provide a good model for investigating invasion in this subset of breast cancers. In the present study we determined that TMX2-28 lack MMP 1 mRNA, and MMP 2/MMP 9 protein expression; each of which are important in protease-dependent invasion. TMX2-28 cells have low expression of other genes key to protease-dependent invasion such as Slug, Snail, N-cadherin, Zeb1, Zeb2, Vimentin and Fibronectin. Conversely, these cells have high expression of protease-independent invasion genes such as Rho, Rock 1, Rock 2, and E-cadherin. Finally, treating TMX2-28 cells with a Rho inhibitor significantly reduces their invasiveness. These data suggest that TMX2-28 cells use a Rho dependent, proteolytic-independent invasion mechanism. Targeting the Rho pathway in TN and basal-like cancer cells that have a proteolytic-independent invasion mechanism may provide therapeutic strategies for the treatment of cancer patients with increased risk of metastasis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1403. doi:10.1158/1538-7445.AM2011-1403