Breast cancer metastasis suppressor-1 differentially modulates growth factor signaling.
That metastatic tumor cells grow in selective non-native environments suggests an ability to differentially respond to local microenvironments. BRMS1, like other metastasis suppressors, halts ectopic growth (metastasis) without blocking orthotopic tumor formation. BRMS1-expressing tumor cells reach secondary sites but do not colonize distant tissues, compelling the hypothesis that BRMS1 selectively restricts the ability of tumor cells to respond to exogenous regulators in different tissues. Here we report that BRMS1 expression in metastatic human breast cancer cells leads to a selective reduction in epidermal growth factor receptor expression and downstream (AKT) signaling. Signaling through another receptor tyrosine kinase, hepatocyte growth factor receptor (c-Met), remains unaltered despite reduced levels of the signaling intermediate phosphatidylinositol (4,5)-bisphosphate. Interestingly, reduced downstream calcium signaling is observed following treatment with platelet-derived growth factor, consistent with decreased phosphatidylinositol (4,5)-bisphosphate. However, platelet-derived growth factor receptor expression is unaltered. Thus, BRMS1 differentially attenuates cellular responses to mitogenic signals, not only dependent upon the specific signal received, but at varying steps within the same signaling cascade. Specific modulation of signaling responses received from the microenvironment may ultimately dictate which environments are permissive/restrictive for tumor cell growth and provide insights into the biology underlying metastasis.
Vaidya
Kedar S
KS
Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
Harihar
Sitaram
S
Phadke
Pushkar A
PA
Stafford
Lewis J
LJ
Hurst
Douglas R
DR
Hicks
David G
DG
Casey
Graham
G
DeWald
Daryll B
DB
Welch
Danny R
DR
D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008934:Mitogens; D008954:Models, Biological; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000737:chemistry; D010766:Phosphorylation; D017978:Receptors, Growth Factor / Q000378:metabolism; D012097:Repressor Proteins; D015398:Signal Transduction; D013997:Time Factors; D014158:Transcription, Genetic
C410024:BRMS1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D008934:Mitogens; D009363:Neoplasm Proteins; D019269:Phosphatidylinositol 4,5-Diphosphate; D017978:Receptors, Growth Factor; D012097:Repressor Proteins; D002118:Calcium