Breast cancer metastasis suppressor 1 (BRMS1) attenuates TGF-β1-induced breast cancer cell aggressiveness through downregulating HIF-1α expression.

Abstract

BACKGROUND:

Cancer metastasis is a multi-step event including epithelial-to-mesenchymal transition (EMT). Breast cancer metastasis suppressor 1 (BRMS1) is a novel metastasis suppressor protein without anti-proliferating activity. However, a detailed underlying mechanism by which BRMS1 attenuates cancer cell EMT and invasion remained to be answered. In the present study, we report an additional mechanism by which BRMS1 attenuates Transforming growth factor-beta1 (TGF-β1)-induced breast cancer cell EMT and invasion.

METHODS:

Experimental analysis involving chromosome immunoprecipitation (ChIP) and luciferase reporter assays were used to validate hypoxia inducible factor-1alpha (HIF-1α) as a transcriptional regulator of TWIST1 and Snail. Quantitative RT-PCR was used to analyze transcript expression. Immunoblotting and immunofluorescence were used to analyze protein expression. Matrigel-coated in vitro invasion insert was used to analyze cancer cell invasion.

RESULTS:

BRMS1 strongly inhibited TGF-β1-induced breast cancer cell EMT and invasion. Unexpectedly, we observed that BRMS1 downregulates not only TWIST1 but also Snail expression, thereby inhibiting breast cancer cell invasion. In addition, we provide evidence that HIF-1α is required for Snail and TWIST1 expression. Further, BRMS1 reduced TGF-β1-induced HIF-1α transcript expression through inactivation of nuclear factor kappaB (NF-κB).

CONCLUSION:

Collectively, the present study demonstrates a mechanical cascade of BRMS1 suppressing cancer cell invasion through downregulating HIF-1α transcript and consequently reducing Snail and TWIST1 expression.

• Authors: Kyung Hwa Cho, Seong-Lan Yu, Do Yeun Cho, Chang Gyo Park, Hoi Young Lee
• Journal: BMC cancer (BMC Cancer) Vol. 15 Pg. 829 (10 31 2015) ISSN: 1471-2407 [Electronic] England
• PMID: 26520789 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BRMS1 protein, human
• Hypoxia-Inducible Factor 1, alpha Subunit
• NF-kappa B
• Nuclear Proteins
• RNA, Small Interfering
• Repressor Proteins
• Snail Family Transcription Factors
• TWIST1 protein, human
• Transcription Factors
• Transforming Growth Factor beta1
• Twist-Related Protein 1

Topics

• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Disease Progression
• Epithelial-Mesenchymal Transition (drug effects, genetics)
• Female
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (genetics, metabolism)
• NF-kappa B (metabolism)
• Nuclear Proteins (genetics, metabolism)
• RNA, Small Interfering (genetics)
• Repressor Proteins (genetics, metabolism)
• Snail Family Transcription Factors
• Transcription Factors (genetics, metabolism)
• Transforming Growth Factor beta1 (pharmacology)
• Twist-Related Protein 1 (genetics, metabolism)