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Originally published online as doi:10.2353/ajpath.2010.090383 on December 11, 2009

Published online before print December 11, 2009
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(American Journal of Pathology. 2010;176:446-460.)
© 2010 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2010.090383

CrkII Transgene Induces Atypical Mammary Gland Development and Tumorigenesis

Kelly E. Fathers*, Sonia Rodrigues*, Dongmei Zuo{dagger}{ddagger}, Indrani Vasudeva Murthy§, Michael Hallett§, Robert Cardiff and Morag Park*{dagger}{ddagger}

From the Departments of Biochemistry,* Medicine,{dagger} and Oncology,{ddagger} and the McGill Center for Bioinformatics,§ Rosalind and Morris Goodman Cancer Centre, McGill University, Montréal, Canada; and the Department of Pathology, School of Medicine, University of California Davis, Davis, California

The v-Crk protein was originally isolated as the oncogene fusion product of the CT10 chicken retrovirus. Cellular homologues of v-Crk include Crk, which encodes two alternatively spliced proteins (CrkI and CrkII), and CrkL. Though CrkI/II proteins are elevated in several types of cancer, including breast, the question of whether these Crk adaptor proteins can promote breast cancer has not been addressed. We created a transgenic mouse model that allows the expression of CrkII through the hormonally responsive mouse mammary tumor virus promoter. During puberty, transgenic mice were found to have delayed ductal outgrowth, characterized by increased collagen surrounding the terminal end buds. In post-pubertal mice, precocious ductal branching was observed and associated with increased proliferation. Focal mammary tumors appeared in a subset of animals, with a latency of approximately 15 months. Mouse mammary tumor virus/CrkII tumors showed high levels of Crk protein as well as various cytokeratin markers characteristic of their respective tumor pathologies. This study demonstrates that the precise expression of CrkII is critical for integrating signals for ductal outgrowth and branching morphogenesis during mammary gland development. Furthermore, this study provides evidence for a potential role of CrkII in integrating signals for breast cancer progression in vivo, which has important implications for elevated CrkII observed in human cancer.






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