Abstract 5426: New suppression strategy for human breast cancer invasion and metastasis
Authors: Sultan Ahmed S. , Sherif Zaki A. 
Published: February 2011

Identification of agents that are nontoxic but can delay onset and/or progression of breast cancer, which is the main leading cause of cancer-related deaths among women, is highly desirable. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process and poor prognosis of breast cancer is associated with a high potential of cancer cells invasion and metastasis. We have recently uncovered novel evidence that signal transducers and activators of transcription 5a (Stat5a) and its Janus tyrosine kinase, (Jak2), suppress invasion and promote human breast cancer cells differentiation through inhibition of epithelial-to-mesenchymal dedifferentiation. Here, we have further taken advantage of the combination of Jak2/Stat5a overexpression, HDAC inhibitors, Mistletoe (Viscum album) plant extracts, and/or diallyl trisulfide (DATS), a promising cancer chemopreventive constituent of garlic, as an alternative way to inhibit breast cancer invasion and restore differentiation in vitro and in vivo.

We have expanded our investigation to a panel of human breast cancer cell lines that display different phenotypic and differentiation patterns ranging from poor to high differentiation, including MDA-231, MDA-468, T-47D, MCF-7, BT-20, SKBr3, and ZR-75-1 cell lines.

Cells were pretreated with or without HDAC inhibitors, Mistletoe plant extracts and/or diallyl trisulfide (DATS), and then either mock infected or infected with adenovirus carrying Wild type (Wt-Jak2), Wt-Stat5a, Dominant negative (Dn-Stat5), or a combination of Wt-Jak2 and Wt-Stat5a.

Using three-dimensional (3D) Matrigel model system in vitro, the pretreatment with HDAC inhibitors, Mistletoe plant extracts, and /or DATS synergized with co-expression of Wt-Jak2/Stat5a to promote epithelial differentiation by reversing the mesenchymal phenotype morphology, inducing homotypic adhesion, and inhibiting cell motility and invasiveness.

We have also established xenograft tumor models of MDA-231 and T-47D cell lines respectively in nude mice for in vivo studies. After 4 week, the growth of MDA-231 and T-47D tumors that co-expressing Wt-Jak2/Stat5a was inhibited by 45.4% and 51.12% compared to the mock group (t=2.410, P&lt;0.05) and by 48.3% and 54.33% respectively compared to the tumors expressing Dn-Stat5 group (t=1.994, P&lt;0.05). Furthermore, the pretreatment with HDAC inhibitors and/or DATS significantly inhibited the growth of MDA-231 and T-47D xenografted tumors expressing Wt-Jak2/Stat5a compared to the tumors expressing Wt- Stat5a or Wt-Jak2 alone.

All-in-all, the observations support a novel role of a combination between Jak2/Stat5a overexpression and nontoxic agents that can delay onset and/or progression of breast cancer as a new tool to restore lost differentiation of human breast cancer through EMT inhibition, which could be a new therapeutic strategy to inhibit human breast cancer progression.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5426.