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Breast cancer metastasis suppressor 1 inhibits gene expression by targeting nuclear factor-kappaB activity
Muzaffer Cicek1, Ryuichi Fukuyama, Danny R Welch
1Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic Lerner School of Medicine, Cleveland, Ohio 44195, USA.
Abstract:
Breast cancer metastasis suppressor 1 (BRMS1) functions as a metastasis suppressor gene in breast cancer and melanoma cell lines, but the mechanism of BRMS1 suppression remains unclear. We determined that BRMS1 expression was inversely correlated with that of urokinase-type plasminogen activator (uPA), a prometastatic gene that is regulated at least in part by nuclear factor-kappaB (NF-kappaB). To further investigate the role of NF-kappaB in BRMS1-regulated gene expression, we examined NF-kappaB binding activity and found an inverse correlation between BRMS1 expression and NF-kappaB binding activity in MDA-MB-231 breast cancer and C8161.9 melanoma cells stably expressing BRMS1. In contrast, BRMS1 expression had no effect on activation of the activator protein-1 transcription factor. Further, we showed that suppression of both constitutive and tumor necrosis factor-alpha-induced NF-kappaB activation by BRMS1 may be due to inhibition of IkappaBalpha phosphorylation and degradation. To examine the relationship between BRMS1 and uPA expression in primary breast tumors, we screened a breast cancer dot blot array of normalized cDNA from 50 breast tumors and corresponding normal breast tissues. There was a significant reduction in BRMS1 mRNA expression in breast tumors compared with matched normal breast tissues (paired t test, P < 0.0001) and a general inverse correlation with uPA gene expression (P < 0.01). These results suggest that at least one of the underlying mechanisms of BRMS1-dependent suppression of tumor metastasis includes inhibition of NF-kappaB activity and subsequent suppression of uPA expression in breast cancer and melanoma cells.
Insights
Breast cancer metastasis suppressor 1 (BRMS1) inhibits tumor spread by suppressing nuclear factor-kappaB (NF-kappaB) activity. This mechanism reduces urokinase-type plasminogen activator (uPA) expression, a key factor in metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Gene Regulation
Background:
- Breast cancer metastasis suppressor 1 (BRMS1) is a known metastasis suppressor.
- The precise molecular mechanisms underlying BRMS1's suppressive function are not fully understood.
- Urokinase-type plasminogen activator (uPA) is a prometastatic gene implicated in cancer progression.
Purpose of the Study:
- To elucidate the mechanism by which BRMS1 suppresses metastasis.
- To investigate the relationship between BRMS1, nuclear factor-kappaB (NF-kappaB), and urokinase-type plasminogen activator (uPA) expression.
- To determine if BRMS1 affects NF-kappaB activity in breast cancer and melanoma cells.
Main Methods:
- Assessed NF-kappaB binding activity in cell lines stably expressing BRMS1.
- Examined the effect of BRMS1 on activator protein-1 (AP-1) transcription factor.
- Investigated BRMS1's impact on IkappaBalpha phosphorylation and degradation.
- Analyzed BRMS1 and uPA mRNA expression in primary breast tumors using a dot blot array.
Main Results:
- BRMS1 expression inversely correlated with NF-kappaB binding activity in breast cancer and melanoma cells.
- BRMS1 suppressed both constitutive and TNF-alpha-induced NF-kappaB activation, potentially by inhibiting IkappaBalpha phosphorylation/degradation.
- BRMS1 expression was significantly reduced in primary breast tumors compared to normal tissues.
- A general inverse correlation was observed between BRMS1 and uPA gene expression in breast tumors.
Conclusions:
- BRMS1 suppresses tumor metastasis, at least partly, by inhibiting NF-kappaB activity.
- This inhibition leads to subsequent suppression of uPA expression in breast cancer and melanoma.
- BRMS1's role in downregulating NF-kappaB and uPA presents a potential therapeutic target for reducing breast cancer metastasis.
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