Alternative suppression strategy for human breast cancer invasion and metastasis: a potential for a new differentiation therapy.

Abstract

Abstract Abstract #2059 Poor prognosis of human breast cancer is associated with a high potential of cancer cells invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion process. 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.
 However, the precise mechanism of Jak2/Stat5a role in human breast cancer is still under investigation.
 In this study, we have further critically taken advantage of the combination of Jak2/Stat5a genes expression, HDAC inhibitors, and Mistletoe (Viscum album) plant extracts as an alternative way to suppress breast cancer progression by reversing the mesenchymal phenotype, and restoring homotypic adhesion, and in turn induce tumor differentiation in vitro and in vivo. We have expanded our investigation to involve a highly invasive breast cancer cell line, MDA-231, in addition to BT-20 and T-47D human breast cancer cells that display different phenotypic and differentiation patterns ranging from poor to high differentiation. Cells were pretreated with or without different HDAC inhibitors, and/or Mistletoe (Viscum album) plant extracts, 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 and/or Mistletoe (Viscum album) plant extracts synergized with co-expression of Wt-Jak2/Stat5a genes to promote epithelial differentiation by reversing the mesenchymal phenotype morphology, inducing homotypic adhesion, and inhibiting cell motility and invasiveness.
 We have also established a xenograft tumor model of MDA-231 cells in nude mice for in vivo studies. After 4 week, the growth of MDA-231 tumors that co-expressing Wt-Jak2/Stat5a was inhibited by 47.90% compared to the mock group (t=2.821, P<0.05) and by 52.86% compared to the tumors expressing Dn-Stat5 group (t=2.394, P<0.05). Furthermore, the pretreatment with HDAC inhibitors and/or Mistletoe (Viscum album) plant extracts enhanced significantly the growth inhibition of MDA-231 xenografted tumors expressing Wt-Jak2/Stat5a compared to the tumors expressing Wt-Stat5a or Wt-Jak2 alone.
 Collectively, the observations support a novel role of Jak2/Stat5a genes as a new tool to restore lost differentiation of human breast cancer through inhibiting EMT that could lead to new therapeutic strategies to reverse cancer progression-related changes and introduce alternative cancer treatments in addition to standard chemotherapy and radiation treatment. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 2059.