title: Blockage of heregulin expression inhibits tumorigenicity and metastasis of breast cancer.
abstract: The growth factor heregulin (HRG), expressed in about 30% of breast cancer tumors, activates the erbB-2 receptor via induction of heterodimeric complexes of erbB-2 with erbB-3 or erbB-4. HRG induces tumorigenicity and metastasis of breast cancer cells. Our investigation into whether HRG is a factor likely to promote tumor formation independently of erbB-2 overexpression concludes that blockage of HRG expression suppresses the aggressive phenotype of MDA-MB-231 breast cancer cells by inhibiting cell proliferation, preventing anchorage-independent growth, and suppressing the invasive potential of the cells in vitro. More importantly, we observed a marked reduction in tumor formation, tumor size, and a lack of metastasis in vivo. These studies were achieved by blocking HRG expression in MDA-MB-231 cells using an HRG antisense cDNA. In the search for the mechanism by which blockage of HRG reverts this aggressive phenotype, we discovered that the cells in which HRG is blocked exhibit a marked decrease in erbB activation and a significant reduction in MMP-9 activity, demonstrating a direct causal role in HRG induction of tumorigenicity. Our study is the first report and serves as a proof of the concept that HRG is a key promoter of breast cancer tumorigenicity and metastasis independently of erbB-2 overexpression and should be deemed a potential target in developing therapies for breast cancer.
authors.affiliation: Ernest Orlando Lawrence Berkeley National Laboratory, University of California, 94720, USA.
authors.forename: Miaw-Sheue
authors.initials: MS
authors.lastname: Tsai
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Shamon-Taylor
authors.forename: Inderjit
authors.initials: I
authors.lastname: Mehmi
authors.forename: Careen K
authors.initials: CK
authors.lastname: Tang
authors.forename: Ruth
authors.initials: R
authors.lastname: Lupu
mesh_terms: D001943:Breast Neoplasms / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic; D005260:Female; D018734:Genes, erbB-2 / Q000502:physiology; D006801:Humans; D020782:Matrix Metalloproteinases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology; D009362:Neoplasm Metastasis; D020890:Neuregulin-1 / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D020890:Neuregulin-1; D020928:Mitogen-Activated Protein Kinases; D020782:Matrix Metalloproteinases