BRMS1 suppresses breast cancer experimental metastasis to multiple organs by inhibiting several steps of the metastatic process.
Breast cancer metastasis suppressor 1 (BRMS1) inhibits formation of macroscopic lung metastases in breast, ovary, and melanoma xenograft models. Because it is unclear which step(s) of the metastatic cascade are affected by BRMS1, the major aim of this study was to determine when and how BRMS1 acts to suppress metastasis. We also examined whether BRMS1 expression globally blocks metastasis or selectively inhibits metastatic outgrowths in specific tissues. Metastatic human breast carcinoma cell lines MDA-MB-231 and -435 expressing enhanced green fluorescent protein (GFP; 231 GFP and 435 GFP) and cell lines transduced with the BRMS1 gene (231 GFP-BRMS1 and 435 GFP-BRMS1) were injected into the left cardiac ventricle to achieve the widest possible cellular distribution, by minimizing first-pass clearance in the lungs. Compared with parental cells, BRMS1-expressing clones formed significantly fewer metastases in all organs tested. When cells were injected directly into the vasculature, fewer of the BRMS1-expressing cells reached lungs or bone compared with parental cells, suggesting that restoration of BRMS1 expression increased cell death during transit. Susceptibility to anoikis was verified in vitro by demonstrating decreased survival on poly-hydroxyethyl methacrylate-coated dishes. Most of the BRMS1-expressing cells reaching secondary sites failed to proliferate, suggesting that BRMS1 also inhibits colonization. Coupled with previous reports showing modest effects of BRMS1 on adhesion and invasion, our results indicate that BRMS1 inhibits metastases in multiple organs by blocking several steps in the metastatic cascade.
Phadke
Pushkar A
PA
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294-0019, USA.
Vaidya
Kedar S
KS
Nash
Kevin T
KT
Hurst
Douglas R
DR
Welch
Danny R
DR
D000818:Animals; D023102:Anoikis / Q000235:genetics; D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology*; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology*; D018450:Disease Progression; D005260:Female; D016147:Genes, Tumor Suppressor / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000235:genetics; D012097:Repressor Proteins; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
C410024:BRMS1 protein, human; D009363:Neoplasm Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D049452:Green Fluorescent Proteins