S100A7-downregulation inhibits epidermal growth factor-induced signaling in breast cancer cells and blocks osteoclast formation.
S100A7 is a small calcium binding protein, which has been shown to be differentially expressed in psoriatic skin lesions, as well as in squamous cell tumors of the skin, lung and breast. Although its expression has been correlated to HER+ high-grade tumors and to a high risk of progression, the molecular mechanisms of these S100A7-mediated tumorigenic effects are not well known. Here, we showed for the first time that epidermal growth factor (EGF) induces S100A7 expression in both MCF-7 and MDA-MB-468 cell lines. We also observed a decrease in EGF-directed migration in shRNA-downregulated MDA-MB-468 cell lines. Furthermore, our signaling studies revealed that EGF induced simultaneous EGF receptor phosphorylation at Tyr1173 and HER2 phosphorylation at Tyr1248 in S100A7-downregulated cell lines as compared to the vector-transfected controls. In addition, reduced phosphorylation of Src at tyrosine 416 and p-SHP2 at tyrosine 542 was observed in these downregulated cell lines. Further studies revealed that S100A7-downregulated cells had reduced angiogenesis in vivo based on matrigel plug assays. Our results also showed decreased tumor-induced osteoclastic resorption in an intra-tibial bone injection model involving SCID mice. S100A7-downregulated cells had decreased osteoclast number and size as compared to the vector controls, and this decrease was associated with variations in IL-8 expression in in vitro cell cultures. This is a novel report on the role of S100A7 in EGF-induced signaling in breast cancer cells and in osteoclast formation.
Paruchuri
Vikram
V
Division of Experimental Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Prasad
Anil
A
McHugh
Kevin
K
Bhat
Hari K
HK
Polyak
Kornelia
K
Ganju
Ramesh K
RK
D000818:Animals; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D002465:Cell Movement; D049109:Cell Proliferation; D002478:Cells, Cultured; D003094:Collagen / Q000378:metabolism; D015536:Down-Regulation; D004338:Drug Combinations; D004815:Epidermal Growth Factor / Q000494:pharmacology*; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D015151:Immunoblotting; D016209:Interleukin-8 / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D051379:Mice; D016513:Mice, SCID; D009389:Neovascularization, Pathologic; D010010:Osteoclasts / Q000166:cytology* / Q000378:metabolism; D010014:Osteolysis; D010766:Phosphorylation; D011509:Proteoglycans / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism
D002135:Calcium-Binding Proteins; D003094:Collagen; D004338:Drug Combinations; D004815:Epidermal Growth Factor; D066246:ErbB Receptors; D016209:Interleukin-8; D007797:Laminin; D011509:Proteoglycans; D018719:Erb-b2 Receptor Tyrosine Kinases; D000075023:S100 Calcium Binding Protein A7; D009418:S100 Proteins; D014443:Tyrosine; C089242:S100A7 protein, human; C506174:S100a7a protein, mouse; C059485:matrigel; C524056:Erbb2 protein, mouse