title: Signal transducers and activators of transcription-3 up-regulates tissue inhibitor of metalloproteinase-1 expression and decreases invasiveness of breast cancer.
abstract: Signal transducers and activators of transcription (STAT)-3 is an oncogenic protein that is constitutively activated in many human cancers, including 30 to 60% of primary breast cancer. The biological significance of STAT3 activation in breast cancer is not fully understood. We have previously shown that STAT3 up-regulates tissue inhibitors of metalloproteinase (TIMP)-1, a cytokine known to block metalloproteinases and decrease invasiveness in certain cancer cell types. We hypothesize that STAT3 activation may modulate tumor invasiveness of breast cancer by regulating TIMP1 expression. Using MCF-7 cells transfected with tetracycline-off STAT3C (constitutively active STAT3), we generated an in vitro system in which STAT3C levels can be tightly controlled in breast cancer cells. Increasing tetracycline levels gradually decreased STAT3C and TIMP1 in a dose-dependent manner, and down-regulation of these proteins led to a reciprocal decrease in invasiveness of these cells in Matrigel. Addition of a neutralizing anti-TIMP1 antibody increased invasiveness in the same experimental system. Using immunohistochemistry and 142 primary breast tumors, we found a significant association between the expression of the phosphorylated/active form of STAT3 (pSTAT3) and that of TIMP1. Importantly, STAT3 activation correlated significantly with a lower frequency of vascular and lymphatic invasion (P = 0.015 and P = 0.0002, respectively). Our data support the concept that STAT3 activation significantly modulates the biological and clinical behavior of breast cancer.
authors.affiliation: Department of Laboratory Medicine and Pathology, University of Alberta, 4B1, 8440 112 St., Edmonton, Alberta, Canada.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Dien
authors.forename: Hesham M
authors.initials: HM
authors.lastname: Amin
authors.forename: Neil
authors.initials: N
authors.lastname: Chiu
authors.forename: Winson
authors.initials: W
authors.lastname: Wong
authors.forename: Christine
authors.initials: C
authors.lastname: Frantz
authors.forename: Brian
authors.initials: B
authors.lastname: Chiu
authors.forename: John R
authors.initials: JR
authors.lastname: Mackey
authors.forename: Raymond
authors.initials: R
authors.lastname: Lai
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001808:Blood Vessels / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D008208:Lymphatic System / Q000473:pathology; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
chemical_list: D050796:STAT3 Transcription Factor; D019715:Tissue Inhibitor of Metalloproteinase-1