Abstract B42: Jak2/Stat5a overexpression synergizes with mistletoe (Viscum album) extracts, and/or diallyl trisulfide (DATS) to inhibit breast cancer stem cell characteristics, epithelial-mesenchymal transition, and invasion potential.
Authors: Sultan Ahmed S. , Sherif Zaki A. 
Published: June 2012

Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process and poor prognosis of breast cancer, the main leading cause of cancer-related deaths among women, is associated with a high potential of cancer cells invasion and metastasis. Recently, a growing body of evidence is supporting the idea that human breast cancer can be considered as a stem cell disease and the metastatic cell state is strongly correlated to (EMT) and the CD44+/CD24- stem cell phenotype. We have recently uncovered novel evidence that signal transducers and activators of transcription 5a (Stat5a) and its Janus tyrosine kinase, (Jak2), suppress early invasion and promote human breast cancer cells differentiation through inhibition of (EMT) dedifferentiation.

Understanding and identifying the role of Prolactin/Stat5a/Jack2 pathway in the process of early metastasis and differences between invasive and non-invasive breast cancer related to (EMT) or CD44+/CD24- breast cancer stem cell (BCSC) characteristics could lead to more effective treatment.

In the present study, a comparative analysis of epithelial and mesenchymal marker expression was performed, using a panel of human breast cancer cell lines that display different phenotypic and differentiation patterns ranging from poor to high differentiation and expressing different levels of CD44+/CD24- (BCSC) characteristics, such as MDA-231, MDA-468, MDA-157, T-47D, MCF-7, BT-20, SKBr3, and ZR-75–1 cell lines.

Gene expression profiles of the tested cell lines were examined to identify a set of genes that could play a role in (EMT) and evaluated by RT-PCR and flow Cytometry. Our data indicated that human breast cancer cell lines contain a small population of CD44+/CD24- (BCSC) and their self-renewal capacity is inhibited by overexpression of Jak2/Stat5a signaling combined with Mistletoe (Viscum album) plant extracts and/or diallyl trisulfide (DATS) pre-treatment. Our data showed that the increased invasive potential was proportional to increased CD44 expression and downregulated CD24 expression. Using specific CD44 antibody treatment significantly decreased (EMT) and cell invasion potential in MDA-MB-231, MDA-468 and MDA-157 cells. Moreover, Jak2/Stat5a overexpressing cells synergizes with diallyl trisulfide (DATS) in apoptosis induction by activating capase-3 and inhibiting the expression of Bcl-2 in CD44+/CD24- (BCSC) population. Furthermore, the cell lines that overexpressing Jak2/Stat5a and pretreated with (DATS) inhibits (EMT) by blocking the expression of nuclear -catenin, vimentin, slug, and snail, and also decreased population of CD44+/CD24- (BCSC) invasion capacity by induction of E-cadherin expression, suggesting the blockade of signaling involved in early process of metastasis through elimination of cancer stem cell-characteristics.

All-in-all, our data 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 strategy to inhibit (EMT) and in turn breast cancer invasion through inhibition of the CD44+/CD24- (BCSC) characteristics.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B42.