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Negative regulation of BRCA1 by transforming acidic coiled-coil protein 3 (TACC3)
Jung-Lye Kim1, Geun-Hyoung Ha1, Loredana Campo1
1Department of Radiation Oncology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL, 60153, USA.
Abstract:
In spite of the push to identify modifiers of BRCAness, it still remains unclear how tumor suppressor BRCA1 is lost in breast cancers in the absence of genetic or epigenetic aberrations. Mounting evidence indicates that the transforming acidic coiled-coil 3 (TACC3) plays an important role in the centrosome-microtubule network during mitosis and gene expression, and that deregulation of TACC3 is associated with breast cancer. However, the molecular mechanisms by which TACC3 contributes to breast cancer development have yet to be elucidated. Herein, we found that high levels of TACC3 in human mammary epithelial cells can cause genomic instability possibly in part through destabilizing BRCA1. We also found that high levels of TACC3 inhibited the interaction between BRCA1 and BARD1, thus subsequently allowing the BARD1-uncoupled BRCA1 to be destabilized by ubiquitin-mediated proteosomal pathway. Moreover, there is an inverse correlation between TACC3 and BRCA1 expression in breast cancer tissues. Overall, our findings provide a new insight into the role of TACC3 in genomic instability and breast tumorigenesis.
Insights
High levels of transforming acidic coiled-coil 3 (TACC3) destabilize tumor suppressor BRCA1 by disrupting its interaction with BARD1. This mechanism contributes to genomic instability and breast cancer development.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The loss of tumor suppressor BRCA1 function is critical in breast cancer, but mechanisms independent of genetic/epigenetic alterations are unclear.
- Transforming acidic coiled-coil 3 (TACC3) is implicated in breast cancer, yet its precise role in tumorigenesis requires elucidation.
Purpose of the Study:
- To investigate the molecular mechanisms by which TACC3 contributes to breast cancer development.
- To explore the relationship between TACC3, BRCA1, and genomic instability.
Main Methods:
- Assessing the impact of high TACC3 levels on BRCA1 stability in human mammary epithelial cells.
- Investigating the interaction between BRCA1 and BARD1 in the presence of elevated TACC3.
- Analyzing the correlation between TACC3 and BRCA1 expression in breast cancer tissues.
Main Results:
- Elevated TACC3 levels induce genomic instability, potentially by destabilizing BRCA1.
- High TACC3 inhibits the BRCA1-BARD1 interaction, leading to BRCA1 degradation via the ubiquitin-proteasome pathway.
- An inverse correlation exists between TACC3 and BRCA1 expression in human breast cancer tissues.
Conclusions:
- TACC3 plays a significant role in promoting genomic instability and breast tumorigenesis.
- TACC3-mediated destabilization of BRCA1 offers a novel mechanism contributing to breast cancer development.
- Targeting TACC3 may represent a therapeutic strategy for breast cancers with altered BRCA1 function.
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