title: An essential role of metalloprotease-disintegrin ADAM12 in triple-negative breast cancer.
abstract: In the absence of HER2 overexpression, triple-negative breast cancers (TNBCs) rely on signaling by epidermal growth factor receptor (EGFR/ErbB1/HER1) to convey growth signals and stimulate cell proliferation. Soluble EGF-like ligands are derived from their transmembrane precursors by ADAM proteases, but the identity of the ADAM that is primarily responsible for ligand release and activation of EGFR in TNBCs is not clear. Using publicly available gene expression data for patients with lymph node-negative breast tumors who did not receive systemic treatment, we show that ADAM12L is the only ADAM with an expression level significantly associated with decreased distant metastasis-free survival times. Similar effect was not observed for patients with ER-negative non-TNBCs. There was a positive correlation between ADAM12L and HB-EGF and EGFR in TNBCs, but not in ER-negative non-TNBCs. We further demonstrate that ectopic expression of ADAM12L increased EGFR phosphorylation in a mouse intraductal xenograft model of early breast cancer. Finally, we detect strong correlation between the level of anti-ADAM12L and anti-phospho-EGFR immunostaining in human breast tumors using tissue microarrays. These studies suggest that ADAM12L is the primary protease responsible for the activation of EGFR in early stage, lymph node-negative TNBCs. Thus, our results may provide novel insight into the biology of TNBC.
authors.affiliation: Department of Biochemistry, Kansas State University, Chalmers Hall 141, Manhattan, KS 66506, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Li
authors.forename: Sara
authors.initials: S
authors.lastname: Duhachek-Muggy
authors.forename: Yue
authors.initials: Y
authors.lastname: Qi
authors.forename: Yan
authors.initials: Y
authors.lastname: Hong
authors.forename: Fariba
authors.initials: F
authors.lastname: Behbod
authors.forename: Anna
authors.initials: A
authors.lastname: Zolkiewska
mesh_terms: D051722:ADAM Proteins / Q000235:genetics* / Q000378:metabolism; D000072199:ADAM12 Protein; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000473:pathology; D066246:ErbB Receptors / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008198:Lymph Nodes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D010766:Phosphorylation; D011379:Prognosis; D011960:Receptors, Estrogen / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D008565:Membrane Proteins; D011960:Receptors, Estrogen; C512478:EGFR protein, human; D066246:ErbB Receptors; D051722:ADAM Proteins; D000072199:ADAM12 Protein; C000606480:ADAM12 protein, human