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Updated: Jul 3, 2026
Studying TGF-β Signaling and TGF-β-induced Epithelial-to-mesenchymal Transition in Breast Cancer and Normal Cells
Published on: October 27, 2020
Breast cancer metastasis suppressor-1 differentially modulates growth factor signaling
Kedar S Vaidya1, Sitaram Harihar, Pushkar A Phadke
1Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama 35294-0019, USA.
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.
Insights
Metastasis suppressor BRMS1 selectively reduces tumor cell response to growth signals like epidermal growth factor, preventing colonization in new environments. This targeted attenuation of signaling pathways offers insights into metastasis restriction.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Metastatic tumor cells exhibit differential responses to microenvironments, suggesting selective adaptation.
- Metastasis suppressors like BRMS1 inhibit growth in ectopic sites without affecting primary tumor formation.
- BRMS1's mechanism is hypothesized to involve selective restriction of tumor cell responses to external regulators.
Purpose of the Study:
- To investigate how BRMS1 expression affects metastatic human breast cancer cells' response to microenvironmental signals.
- To determine the specific signaling pathways modulated by BRMS1 in the context of metastasis.
Main Methods:
- Analyzing epidermal growth factor receptor (EGFR) and AKT signaling in BRMS1-expressing breast cancer cells.
- Assessing signaling through hepatocyte growth factor receptor (c-Met) and its intermediates.
- Evaluating downstream calcium signaling and receptor expression after platelet-derived growth factor (PDGF) treatment.
Main Results:
- BRMS1 expression selectively reduces epidermal growth factor receptor (EGFR) and downstream AKT signaling.
- Signaling via c-Met remains unaffected, despite altered phosphatidylinositol (4,5)-bisphosphate levels.
- Reduced calcium signaling is observed with PDGF treatment, though PDGF receptor expression is unchanged.
Conclusions:
- BRMS1 differentially attenuates cellular responses to mitogenic signals, impacting specific pathways and steps within cascades.
- Selective modulation of microenvironmental signaling responses by BRMS1 influences tissue permissiveness for tumor growth.
- Understanding BRMS1's action provides insights into the biological mechanisms governing metastasis.
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