NOTCH4 Is a Potential Therapeutic Target for Triple-negative Breast Cancer

Background/Aim: The prognosis for triple- negative breast cancer (TNBC) is poor. In the present study, we evaluated whether NOTCH4 receptor is a potential new therapeutic target for TNBC. Materials and Methods: In vitro proliferation and invasiveness were evaluated in TNBC cells with or without small-interfering RNA (siRNA) for NOTCH4, and with or without NOTCH4 plasmid transfection. In vivo, MDA-MB-231 cells with or without NOTCH4 siRNA were subcutaneously implanted into the flank regions of mice. The frequency of nuclear translocation of NOTCH4 was assessed by immunohistochemistry in 21 TNBC samples and 46 non-TNBC samples. Results: NOTCH4 inhibition in TNBC cells reduced proliferation and invasiveness, and NOTCH4 overexpression in TNBC cells increased proliferation and invasiveness. NOTCH4 inhibition reduced tumour volume and tumourigenicity of mouse xenografts. TNBC cells had a higher frequency of nuclear translocation of NOTCH4 than other cells. Conclusion: NOTCH4 is a new potential therapeutic target for triple- negative breast cancer. Breast cancer continues to be a leading cause of cancer- related death among women worldwide (1), even though it is a cancer for which many standardized adjuvant therapies are available. Of the different types of breast cancer, triple- negative breast cancer (TNBC) accounts for 15% of all breast cancers and has the worst prognosis compared to other breast cancer subtypes: luminal-A, luminal-B, estrogen receptor (ER)-negative/progesterone receptor (PR)-negative/ human epidermal growth factor receptor-2 (HER2)-positive and normal-like subtypes (2). One reason for the poor prognosis of TNBC may be the lack of therapeutic targets such as ER, PR and HER2 when chemoresistance arises, although the chemotherapy response rate is relatively high. Consequently, development of an effective therapeutic strategy for TNBC is urgently required.