title: Bone sialoprotein mediates the tumor cell-targeted prometastatic activity of transforming growth factor beta in a mouse model of breast cancer.
abstract: Transforming growth factor betas (TGF-beta) play a dual role in carcinogenesis, functioning as tumor suppressors early in the process, and then switching to act as prometastatic factors in late-stage disease. We have previously shown that high molecular weight TGF-beta antagonists can suppress metastasis without the predicted toxicities. To address the underlying mechanisms, we have used the 4T1 syngeneic mouse model of metastatic breast cancer. Treatment of mice with a monoclonal anti-TGF-beta antibody (1D11) significantly suppressed metastasis of 4T1 cells to the lungs. When metastatic 4T1 cells were recovered from lungs of 1D11-treated and control mice, the most differentially expressed gene was found to be bone sialoprotein (Bsp). Immunostaining confirmed the loss of Bsp protein in 1D11-treated lung metastases, and TGF-beta was shown to regulate and correlate with Bsp expression in vitro. Functionally, knockdown of Bsp in 4T1 cells reduced the ability of TGF-beta to induce local collagen degradation and invasion in vitro, and treatment with recombinant Bsp protected 4T1 cells from complement-mediated lysis. Finally, suppression of Bsp in 4T1 cells reduced metastasis in vivo. We conclude that Bsp is a plausible mediator of at least some of the tumor cell-targeted prometastatic activity of TGF-beta in this model and that Bsp expression in metastases can be successfully suppressed by systemic treatment with anti-TGF-beta antibodies.
authors.affiliation: Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, MD 20892-5055, USA.
authors.forename: Jeong-Seok
authors.initials: JS
authors.lastname: Nam
authors.forename: Adam M
authors.initials: AM
authors.lastname: Suchar
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Kang
authors.forename: Christina H
authors.initials: CH
authors.lastname: Stuelten
authors.forename: Binwu
authors.initials: B
authors.lastname: Tang
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Michalowska
authors.forename: Larry W
authors.initials: LW
authors.lastname: Fisher
authors.forename: Neal S
authors.initials: NS
authors.lastname: Fedarko
authors.forename: Alka
authors.initials: A
authors.lastname: Jain
authors.forename: Jan
authors.initials: J
authors.lastname: Pinkas
authors.forename: Scott
authors.initials: S
authors.lastname: Lonning
authors.forename: Lalage M
authors.initials: LM
authors.lastname: Wakefield
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000502:physiology; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D058574:Integrin-Binding Sialoprotein; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D012795:Sialoglycoproteins / Q000096:biosynthesis* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; C546872:Ibsp protein, mouse; D058574:Integrin-Binding Sialoprotein; D012795:Sialoglycoproteins; D016212:Transforming Growth Factor beta; D003094:Collagen