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Building Up a High-throughput Screening Platform to Assess the Heterogeneity of HER2 Gene Amplification in Breast Cancers
Published on: December 5, 2017
LMO4 mediates trastuzumab resistance in HER2 positive breast cancer cells
Keshuo Ding1, Zhengsheng Wu1, Xiaocan Li2
1Department of Pathology, Anhui Medical University Hefei, Anhui, P. R. China.
Abstract:
Breast cancer is the leading cause of cancer-related mortality in women worldwide. Trastuzumab (Herceptin) is an effective antibody drug for HER2 positive breast cancer; de novo or acquired trastuzumab resistance retarded the use of trastuzumab for at least 70% of HER2 positive breast cancers. In this study, we reported LMO4 (a member of LIM-only proteins) promoted trastuzumab resistance in human breast cancer cells. Over-expression of LMO4 was observed in acquired trastuzumab resistance breast cancer cells SKBR3 HR and BT474 HR. Depletion of LMO4 partly abolished the trastuzumab resistance of SKBR3 HR and BT474 HR cells. Forced expression of LMO4 significantly increased trastuzumab resistance of HER2 positive breast cancer cells both in vitro and in vivo. BCL-2 was regulated by LMO4 and mediated the promoting role of LMO4 in trastuzumab resistance of HER2 positive breast cancer cells. High level of LMO4 was associated with worse clinicopathological parameters (including tumor size and histological grade) and lower survival rate in HER2 positive breast cancer patients. LMO4 therefore could be used as a target to develop diagnostic and therapeutic methods for human HER2 positive breast cancer.
Insights
LMO4 promotes trastuzumab resistance in HER2 positive breast cancer, hindering treatment effectiveness. Targeting LMO4 may offer new diagnostic and therapeutic strategies for breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Breast cancer is a leading cause of cancer mortality in women globally.
- Trastuzumab is effective for HER2 positive breast cancer, but resistance limits its use.
- Understanding resistance mechanisms is crucial for improving breast cancer treatment outcomes.
Purpose of the Study:
- To investigate the role of LMO4 in trastuzumab resistance in HER2 positive breast cancer.
- To explore LMO4 as a potential therapeutic target for overcoming trastuzumab resistance.
Main Methods:
- Over-expression and depletion of LMO4 in human breast cancer cell lines (SKBR3 HR, BT474 HR).
- In vitro and in vivo experiments to assess trastuzumab resistance.
- Analysis of BCL-2 regulation by LMO4.
- Correlation analysis of LMO4 levels with clinicopathological parameters and patient survival.
Main Results:
- LMO4 is over-expressed in acquired trastuzumab-resistant breast cancer cells.
- LMO4 depletion partially reversed trastuzumab resistance.
- Forced LMO4 expression increased trastuzumab resistance both in vitro and in vivo.
- LMO4 regulates BCL-2, mediating its role in resistance.
- High LMO4 levels correlate with adverse clinicopathological features and reduced survival in HER2 positive breast cancer patients.
Conclusions:
- LMO4 promotes trastuzumab resistance in HER2 positive breast cancer by regulating BCL-2.
- LMO4 is a potential biomarker for predicting treatment response and prognosis.
- Targeting LMO4 presents a promising strategy for overcoming trastuzumab resistance in breast cancer.
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