Description:
Abstract Cancer cells with stem cell-like characteristics are defined as cancer stem cells (CSCs) that are proposed to drive tumor initiation, progression and recurrence. Recent studies show the significance of epithelial-mesenchymal transition (EMT) in the induction of CSCs and their metastatic dissemination. Growth and colonization of the migrating stem cells require their re-differentiation and the reversal of EMT, mesenchymal to epithelial transition (MET), at the site of distant metastasis. We study the functional interplay between two related transcription factors, signal transducer and activator of transcription 5 (Stat5) and Stat3 in the genetic and epigenetic regulation of non-metastatic and metastatic breast cancer cells. Simultaneous activity of both Stats is observed in high percentage of human luminal breast cancers. In both normal and malignant cells, Stat5 activity is associated with cell proliferation, differentiation and survival, however, its activity in tumors is defined as a good prognostic marker due to response to antiestrogen therapy. During postlactational gland regression, called involution, P-Stat3 regulates lysosomal-mediated cell death, which is in contrast to its strong oncogenic function during mammary tumorigenesis. To gain insights into oncogenic functions of Stat5, we established a new mouse model which allows the investigation of genetic and epigenetic contributions in the initiation and progression of mammary tumors. In this model we used genetic manipulation of mammary stem cells (MaSCs) derived from primary tissue and the reconstitution of functional epithelium through transplantation into cleared fat pads to generate transgenic glands. The persistent activation of Stat5 during post-lactational involution resulted in the induction of non-metastatic adenocarcinomas, resembling human luminal-A breast cancer subtype. These tumors could be serially transplanted in BALB/c wild-type recipient mice and contain a small fraction of Lin-CD24lowCD44high tumor initiating cells. Both primary and secondary tumors show simultaneous activity of Stat5 and Stat3 and express estrogen and progesterone receptors (ER+PR+) and their downstream target genes like amphiregulin, RANKL and Wnt4. We performed microarray gene expression analysis of tumor tissues and P-Stat5 transgenic grafts and studied potential target genes, which can explain Stat5 oncogenic functions in tumor formation in contrast to its suppression effects on tumor cell migration. We are now studying the relative contribution of Stat5 and Stat3 in the regulation of metastatic process and transient EMT-MET changes. Our tumor model allows the identification of new genetic and epigenetic biomarkers, which are necessary for a better diagnosis and treatment of breast cancer and the prediction of invasive relapse. Citation Format: Vida Vafaizadeh, Bernd Groner. The functional interplay between activated Stat5 and Stat3 in breast cancer formation and progression. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5003. doi:10.1158/1538-7445.AM2013-5003