ERK and PI3K regulate different aspects of the epithelial to mesenchymal transition of mammary tumor cells induced by truncated MUC1.
Epithelial to mesenchymal transition (EMT) integrates changes to cell morphology and signaling pathways resulting from modifications to the cell's transcriptional response. Different combinations of stimuli ignite this process in the contexts of development or tumor progression. The human MUC1 gene encodes multiple alternatively spliced forms of a polymorphic oncoprotein that is aberrantly expressed in epithelial malignancies. MUC1 is endowed with various signaling modules and has the potential to mediate proliferative and morphological changes characteristic of the progression of epithelial tumors. The tyrosine-rich cytoplasmic domain and the heavily glycosylated extracellular domain both play a role in MUC1-mediated signal transduction. However, the attribution of function to specific domains of MUC1 is difficult due to the concomitant presence of multiple forms of the protein, which stem from alternative splicing and proteolytic cleavage. Here we show that DA3 mouse mammary tumor cells stably transfected with a truncated genomic fragment of human MUC1 undergo EMT. In their EMT, these cells demonstrate altered [i] morphology, [ii] signaling pathways and [iii] expression of epithelial and mesenchymal markers. Similarly to well characterized human breast cancer cell lines, cells transfected with truncated MUC1 show an ERK-dependent increased spreading on fibronectin, and a PI3K-dependent enhancement of their proliferative rate.
Horn
Galit
G
Department of Cell Research and Immunology, George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv 69978, Israel.
Gaziel
Avital
A
Wreschner
Daniel H
DH
Smorodinsky
Nechama I
NI
Ehrlich
Marcelo
M
D000818:Animals; D001483:Base Sequence; D001943:Breast Neoplasms / Q000503:physiopathology*; D002460:Cell Line; D049109:Cell Proliferation; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D005434:Flow Cytometry; D017353:Gene Deletion; D020869:Gene Expression Profiling; D055785:Gene Knockdown Techniques; D006801:Humans; D015151:Immunoblotting; D008648:Mesoderm / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008969:Molecular Sequence Data; D018396:Mucin-1 / Q000235:genetics / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology*
C060192:MUC1 protein, human; D018396:Mucin-1; D019869:Phosphatidylinositol 3-Kinases; D048049:Extracellular Signal-Regulated MAP Kinases