FEN1 knockdown improves trastuzumab sensitivity in human epidermal growth factor 2-positive breast cancer cells
Xue Zeng1, Xiaofang Che1, Yun-Peng Liu1
1Department of Medical Oncology, The First Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China.
Abstract:
Trastuzumab has been widely applied as a treatment for human epidermal growth factor 2 (HER2)-overexpressing breast cancer. However, the therapeutic efficacy of trastuzumab is limited. Flap endonuclease 1 (FEN1) is a multifunctional endonuclease that has a crucial role in DNA recombination and repair. Inhibition of FEN1 is associated with the reversal of anticancer drug resistance. However, it is unclear whether FEN1 is involved in trastuzumab resistance. In the present study, it was demonstrated that trastuzumab increases the expression of FEN1, and FEN1 knockdown significantly enhanced the sensitivity of BT474 cells to trastuzumab (P<0.05). It was also revealed that trastuzumab induced HER receptor activation, increased binding with FEN1 and estrogen receptor α (ERα), and upregulated ERα-target gene transcription (P<0.05). Upon silencing of FEN1 expression with siRNA, activation of HER receptor and FEN1 binding to ERα were decreased, and trastuzumab-induced ERα target gene upregulation was partially ameliorated (P<0.05). These results suggest that FEN1 may mediate trastuzumab resistance via inducing HER receptor activation and enhancing ERα-target gene transcription. The findings of the present study indicate a novel role of FEN1 in trastuzumab resistance, suggesting that targeting FEN1 may enhance the efficiency of trastuzumab as a treatment for HER2-positive breast cancer.
Insights
Flap endonuclease 1 (FEN1) may drive trastuzumab resistance in HER2-positive breast cancer by activating HER receptors and estrogen receptor alpha (ERα) target genes. Targeting FEN1 could improve trastuzumab treatment efficacy.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Trastuzumab is a key treatment for HER2-overexpressing breast cancer, but resistance limits its effectiveness.
- Flap endonuclease 1 (FEN1) plays roles in DNA repair and its inhibition can reverse anticancer drug resistance.
- The role of FEN1 in trastuzumab resistance remains largely unexplored.
Purpose of the Study:
- To investigate the involvement of FEN1 in trastuzumab resistance in HER2-positive breast cancer.
- To elucidate the molecular mechanisms by which FEN1 might influence trastuzumab efficacy.
- To explore FEN1 as a potential therapeutic target to overcome trastuzumab resistance.
Main Methods:
- Analysis of FEN1 expression in response to trastuzumab treatment.
- FEN1 knockdown using siRNA in BT474 breast cancer cells.
- Assessment of HER receptor activation and FEN1-ERα binding.
- Quantification of ERα-target gene transcription.
Main Results:
- Trastuzumab treatment increased FEN1 expression in BT474 cells.
- FEN1 knockdown significantly enhanced BT474 cell sensitivity to trastuzumab.
- Trastuzumab induced HER receptor activation and FEN1 binding to ERα, upregulating ERα-target genes.
- Silencing FEN1 decreased HER receptor activation and FEN1-ERα binding, partially reversing ERα-target gene upregulation.
Conclusions:
- FEN1 appears to mediate trastuzumab resistance by promoting HER receptor activation and ERα-target gene transcription.
- FEN1 plays a novel role in trastuzumab resistance in HER2-positive breast cancer.
- Targeting FEN1 presents a potential strategy to enhance trastuzumab treatment efficacy.
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