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Inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer
Li Zhao1, Yongjie Ma1, Feng Gu1
1Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Breast Cancer Prevention and Therapy, Tianjin Medical University, Ministry of Education; Key Laboratory of Cancer Prevention and Therapy of Tianjin, Tianjin 300060, China.
Background:
Paclitaxel (PAC) is the first-line chemotherapy drug for most breast cancer patients, but clinical studies showed that some breast cancer patients were insensitive to PAC, which led to chemotherapy failure. It was reported that Notch1 signaling participated in drug resistance of breast cancer. Here, we show whether Notch1 expression is related to PAC sensitivity of breast cancer.
Methods:
We employed Notch1 siRNA and Notch1 inhibitor, N-[N-(3,5-difluorophenacetyl)-1-alanyl]-S-phenylglycine t-butylester (DAPT), to down regulate Notch1 expression in human breast cancer cells MDA-MB-231, and detected the inhibition effect by Western blotting and reverse trans cription-polymerase chain reaction, respectively. After 24 hours exposure to different concentration of PAC (0, 1, 5, 10, 15, 20, and 25 µg/ml), the viability of the control group and experimental group cells was tested by MTT. We also examined the expression of Notch1 in PAC sensitive and nonsensitive breast cancer patients, respectively by immunohistochemistry (IHC). The PAC sensitivity of breast cancer patients were identified by collagen gel droplet embedded culture-drug sensitivity test (CD-DST).
Results:
Down regulation of Notch1 expression by Notch1siRNA interference or Notch1 inhibitor increased the PAC sensitivity in MDA-MB-231 cells (P < 0.05). Also, the expression of Notch1 in PAC sensitive patients was much lower than that of PAC non-sensitive patients (P < 0.01).
Conclusion:
Notch1 expression has an effect on PAC sensitivity in breast cancer patients, and the inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.
Insights
Notch1 signaling pathway affects paclitaxel (PAC) sensitivity in breast cancer. Inhibiting Notch1 expression enhances PAC sensitivity in breast cancer cells and patients, offering a potential therapeutic strategy.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Paclitaxel (PAC) is a primary chemotherapy for breast cancer.
- Chemotherapy failure occurs due to PAC insensitivity in some patients.
- Notch1 signaling is implicated in breast cancer drug resistance.
Purpose of the Study:
- To investigate the relationship between Notch1 expression and paclitaxel (PAC) sensitivity in breast cancer.
- To determine if inhibiting Notch1 can enhance PAC sensitivity.
Main Methods:
- Downregulated Notch1 in MDA-MB-231 cells using siRNA and DAPT.
- Assessed Notch1 inhibition via Western blotting and RT-PCR.
- Measured cell viability using MTT assay after PAC exposure.
- Examined Notch1 expression in patients using immunohistochemistry (IHC) and correlated with drug sensitivity (CD-DST).
Main Results:
- Notch1 downregulation significantly increased PAC sensitivity in breast cancer cells (P < 0.05).
- PAC-insensitive patients exhibited significantly higher Notch1 expression compared to PAC-sensitive patients (P < 0.01).
Conclusions:
- Notch1 expression levels correlate with paclitaxel (PAC) sensitivity in breast cancer.
- Inhibiting Notch1 can enhance PAC sensitivity, suggesting a potential therapeutic approach for overcoming breast cancer chemotherapy resistance.
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