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Identification of a Stat3-Dependent Transcription Regulatory Network Involved in Metastatic Progression

¹ Goodman Cancer Centre, ² Centre for Bioinformatics, Departments of ³ Biochemistry and ⁴ Medicine, and ⁵ School of Computer Science, McGill University, Montreal, Quebec, Canada and ⁶ Departments of Pathology (Experimental) and Microbiology, New York University School of Medicine, New York, New York

Requests for reprints: William J. Muller, McGill University, Cancer Pavilion, Room 509, 1160 Pine Avenue West, Montreal, Quebec, Canada H3G 0B1. Phone: 514-398-5847; Fax: 514-398-6769; E-mail: William.muller{at}mcgill.ca.

Key Words: metastasis • mouse model • Stat3

High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein . [Cancer Res 2009;69(17):6823–30]