Abstract
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.
Highlights
Metastasis suppressors are a growing family of more than 20 proteins that, when re-expressed in metastatic cells, block metastasis without preventing tumor growth at orthotopic sites [3]
BRMS1 Selectively Regulates Growth Factor Receptor Expression—We and others have previously shown that BRMS1-expressing cells grow in orthotopic sites, but not ectopic sites (10 –12)
Metastasis suppression can be explained by fewer BRMS1-expressing cells reaching secondary sites
Summary
Metastasis suppressors are a growing family of more than 20 proteins that, when re-expressed in metastatic cells, block metastasis without preventing tumor growth at orthotopic sites [3]. Membranes were incubated with primary antibodies to epidermal growth factor receptor (EGFR; 2232), p42/p44 mitogen-activated protein kinase (MAPK; 9102), or phospho-p42/p44 MAPK (9101) (Cell Signaling, Danvers, MA) or phospho-AKT-Ser473 (P4112) or AKT (P2482) (Sigma) overnight at 4 °C and subsequently with horseradish peroxidase-conjugated secondary antibody at room temperature for 2 h. BRMS1 Selectively Regulates Growth Factor Receptor Expression—We and others have previously shown that BRMS1-expressing cells grow in orthotopic sites, but not ectopic sites (10 –12).
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