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Knockdown of the Inhibitor of Apoptosis BRUCE Sensitizes Resistant Breast Cancer Cells to Chemotherapeutic Agents
- Source :
- Journal of cancer science & therapy
- Publication Year :
- 2015
- Publisher :
- OMICS Publishing Group, 2015.
-
Abstract
- Background and objectives: Management of patients with breast cancer often fails because of inherent or acquired resistance to chemotherapy. BRUCE (BIR repeat containing ubiquitin-conjugating enzyme) is a member of the inhibitor of apoptosis protein (IAP) family. It has various cellular functions including suppression of apoptosis and promotion of cytokinesis. Furthermore, it pays a critical role in promotion of DNA damage repair and preservation of genome stability, a new function recently reported by our group. Although BRUCE is expressed in breast cancer cell lines, its expression in human primary breast tumors and its contribution to chemoresistance in breast cancers has not been explored. Chemotherapeutic drugs are used in the treatment of breast cancer patients. However, they are not effective to all patients and patients often develop resistance. Consequently we explored if BRUCE protein level, as judged by immunohistochemistry (IHC), is higher in primary breast tumors than normal breast tissue. We also examined if depletion of BRUCE, using a lentiviral shRNA approach, enhances cell sensitivity to multiple chemotherapeutic agents, including cisplatin, an agent that induces DNA damage by generating DNA cross-links, and taxol, a microtubule stabilizer and mitotic inhibitor. The reason for including these two chemotherapeutic agents in this study is that they hit two essential cellular processes of DNA repair and cytokinesis in which BRUCE plays critical roles. Results and methods: IHC analysis of BRUCE revealed significantly higher levels of BRUCE in primary breast tumors than normal breast tissue. Knockdown of BRUCE protein expression by lentiviral shRNA resulted in increased sensitivity to cisplatin in the resistant breast cancer MDB-MD-231 cell line. Moreover, depletion of BRUCE in this cell line achieved a more profound level of cell killing when coupled to low doses of cisplatin and taxol combined, rather than either drug used alone. Conclusions: Our data suggest that elevated protein levels of BRUCE in breast tumors may contribute to chemoresistance in breast cancer patients. In support of this suggestion, our data demonstrate that a reduction in BRUCE expression in breast cancer cell lines increases the toxicity of several chemotherapeutic agents. In all likelihood, the contribution of increased BRUCE levels to chemoresistance are likely due to its roles in suppression of apoptosis, promotion of cytokinesis and facilitation of DNA damage repair. These observations suggest that therapeutic suppression of BRUCE could improve chemosensitivity in chemo-resistant breast cancer patients. Therefore, future development of effective inhibitors of BRUCE could benefit patients with high BRUCE expression and chemoresistance.
- Subjects :
- Cell death
Cancer Research
Programmed cell death
DNA repair
DNA damage
Bioinformatics
Inhibitor of apoptosis
Article
03 medical and health sciences
0302 clinical medicine
Breast cancer
medicine
Chemotherapy
Breast tumors
DNA damage repair and signaling
030304 developmental biology
Cisplatin
0303 health sciences
Breast cancer cells
business.industry
medicine.disease
3. Good health
Inhibitor of apoptosis protein (IAP)
Cell killing
Oncology
Apoptosis
030220 oncology & carcinogenesis
Cancer research
business
human activities
circulatory and respiratory physiology
medicine.drug
Subjects
Details
- ISSN :
- 19485956
- Database :
- OpenAIRE
- Journal :
- Journal of Cancer Science and Therapy
- Accession number :
- edsair.doi.dedup.....2cffe94a121974097100a4af7b038157