Inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.
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).


CONCLUSIONS
Notch1 expression has an effect on PAC sensitivity in breast cancer patients, and the inhibition of Notch1 increases paclitaxel sensitivity to human breast cancer.
Tianjin 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.
Li
L
Zhao
Tianjin 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.
Yongjie
Y
Ma
Tianjin 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. Email: yongjiemagu@aliyun.com.cn.
Feng
F
Gu
Tianjin 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.
Li
L
Fu
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000494:pharmacology; D006801:Humans; D007150:Immunohistochemistry; D017239:Paclitaxel / Q000494:pharmacology*; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D004151:Dipeptides; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; D017239:Paclitaxel