Invasive prostate carcinoma driven by c-Src and androgen receptor synergy.
Cellular Src (c-Src) integrates a large number of signal transduction pathways regulating cell division, migration, and other aspects of cell physiology. Mutations of Src kinase have not been described in human prostate cancer, but evidence for increased levels of expression accompanying cancer progression has been reported. We analyzed overexpression of c-Src in naïve mouse prostate epithelium and observed no change in tubule formation frequency or histologic structure. However, when enhanced c-Src expression is coupled with enhanced expression of androgen receptor (AR), it results in a strong activation of Src kinase activity accompanied by activation of the MAPK pathway, and enhanced AR activity. Similar to the pathology induced by constitutively active c-Src(Y529F), the tubules progress to frank carcinoma with invasion and display markers of epithelial-to-mesenchymal transition. These combined results suggest that nonmutated Src kinase may play a more important role in the genesis and progression of prostate cancer than previously appreciated and that epigenetic changes that enhance the level of AR may select for enhanced expression of c-Src with accompanying activation and a strong drive to malignant progression.
Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA, USA.
Houjian
H
Cai
Ivan
I
Babic
Xiao
X
Wei
Jiaoti
J
Huang
Owen N
ON
Witte
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000069439:Dasatinib; D058750:Epithelial-Mesenchymal Transition; D020935:MAP Kinase Signaling System; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D013844:Thiazoles / Q000494:pharmacology; D015854:Up-Regulation; D019061:src-Family Kinases
D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011944:Receptors, Androgen; D013844:Thiazoles; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human; D020780:Matrix Metalloproteinase 9; D000069439:Dasatinib