title: Integrin-associated CD151 drives ErbB2-evoked mammary tumor onset and metastasis.
abstract: ErbB2+ human breast cancer is a major clinical problem. Prior results have suggested that tetraspanin CD151 might contribute to ErbB2-driven breast cancer growth, survival, and metastasis. In other cancer types, CD151 sometimes supports tumor growth and metastasis. However, a definitive test of CD151 effects on de novo breast cancer initiation, growth, and metastasis has not previously been done. We used CD151 gene-deleted mice expressing the MMTV-ErbB2 transgene to show that CD151 strongly supports ErbB2+ mammary tumor initiation and metastasis. Delayed tumor onset (by 70-100 days) in the absence of CD151 was accompanied by reduced survival of mammary epithelial cells and impaired activation of FAK- and MAPK-dependent pathways. Both primary tumors and metastatic nodules showed smooth, regular borders, consistent with a less invasive phenotype. Furthermore, consistent with impaired oncogenesis and decreased metastasis, CD151-targeted MCF-10A/ErbB2 cells showed substantial decreases in three-dimensional colony formation, EGF-stimulated tumor cell motility, invasion, and transendothelial migration. These CD151-dependent functions were largely mediated through α6β4 integrin. Moreover, CD151 ablation substantially prevented PKC- and EGFR/ERK-dependent α6β4 integrin phosphorylation, consistent with retention of epithelial cell polarity and intermediate filament cytoskeletal connections, which helps to explain diminished metastasis. Finally, clinical data analyses revealed a strong correlation between CD151 and ErbB2 expression and metastasis-free survival of breast cancer patients. In conclusion, we provide strong evidence that CD151 collaborates with LB integrins (particularly α6β4 and ErbB2 (and EGFR) receptors to regulate multiple signaling pathways, thereby driving mammary tumor onset, survival, and metastasis. Consequently, CD151 is a useful therapeutic target in malignant ErbB2+ breast cancer.
authors.affiliation: Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Deng
authors.forename: Qinglin
authors.initials: Q
authors.lastname: Li
authors.forename: John
authors.initials: J
authors.lastname: Hoff
authors.forename: Marian
authors.initials: M
authors.lastname: Novak
authors.forename: Helen
authors.initials: H
authors.lastname: Yang
authors.forename: Hongyan
authors.initials: H
authors.lastname: Jin
authors.forename: Sonia F
authors.initials: SF
authors.lastname: Erfani
authors.forename: Chandan
authors.initials: C
authors.lastname: Sharma
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhou
authors.forename: Isaac
authors.initials: I
authors.lastname: Rabinovitz
authors.forename: Arnoud
authors.initials: A
authors.lastname: Sonnenberg
authors.forename: Yajun
authors.initials: Y
authors.lastname: Yi
authors.forename: Peter
authors.initials: P
authors.lastname: Zhou
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Stipp
authors.forename: David M
authors.initials: DM
authors.lastname: Kaetzel
authors.forename: Martin E
authors.initials: ME
authors.lastname: Hemler
authors.forename: Xiuwei H
authors.initials: XH
authors.lastname: Yang
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005260:Female; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism; D000077341:Lapatinib; D008321:Mammary Glands, Animal / Q000378:metabolism; D015674:Mammary Neoplasms, Animal / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009570:Nitriles / Q000494:pharmacology; D010766:Phosphorylation / Q000235:genetics; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D060185:Tetraspanin 24 / Q000235:genetics / Q000378:metabolism*; D057705:Transendothelial and Transepithelial Migration / Q000187:drug effects
chemical_list: D002070:Butadienes; D004815:Epidermal Growth Factor; D051417:Focal Adhesion Kinase 1; D039161:Integrin alpha6beta4; D000077341:Lapatinib; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D060185:Tetraspanin 24; C113580:U 0126; C508053:ERBB2 protein, human; C524056:Erbb2 protein, mouse; C496051:Ptk2 protein, mouse