Abstract
Background Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. The challenge in managing this heterogeneous malignancy is that BC is highly aggressive and is always associated with chemical resistance, radiation resistance, hormone therapy resistance, and targeted therapy resistance. Therefore, there is an urgent need to find effective drugs to treat BC. Methods Based on the Selleck drug library approved by FDA, we screened 800 drugs for anti-BC cells and found that tegaserod maleate (TM), a 5-hydroxytryptamine 4-receptor (HTR4) partial agonist had the best anti-BC effect, which was further verified. The effects of different concentrations of TM on cell proliferation, invasion, and migration were evaluated in vitro using CCK8, plate cloning, transwell, and scratch assays. The UALCAN database, Kaplan–Meier Plotter database, Human Protein Atlas, and GEPIA2 were used to explore the correlation between HTR4 expression and BC patients' clinicopathological data as well as immune response. In vivo experiments demonstrated the effect of the TM and immunotherapy drug (anti-PD1/anti-TIGIT) combination on BC tumor growth in mice. Results TM significantly inhibited the proliferation, invasion, and migration of BC cells, and the higher the concentration, the better the inhibition effect. HTR4 was significantly downregulated in BC tissues compared to paracancerous tissues. The downregulation of HTR4 was correlated with clinicopathological data and positively correlated with BC prognosis. Interestingly, the GEPIA2 database suggested that there was a strong positive correlation between the expression of HTR4 and effector T cells, effector memory T cells, and exhausted T cells. In vitro experiments showed that TM, anti-PD1, and anti-TIGIT could all inhibit the growth and weight of BC tumors as compared with the control group. However, when anti-PD1 or anti-TIGIT was used simultaneously with TM, the inhibition of tumors significantly exceeded that in the control group. Moreover, the combination of anti-TIGIT and TM has the best inhibitory effect. Conclusion TM inhibited the progression of breast cancer, and its combination with anti-TIGIT could effectively inhibit tumor growth and improve the sensitivity of immunotherapy in breast cancer.
Highlights
BackgroundBreast cancer (BC) is the most commonly diagnosed cancer in women worldwide. e challenge in managing this heterogeneous malignancy is that BC is highly aggressive and is always associated with chemical resistance, radiation resistance, hormone therapy resistance, and targeted therapy resistance. erefore, there is an urgent need to find effective drugs to treat BC
Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide [1], and a complex disease with morphological and molecular heterogeneity, characterized by three morphological grades and more than four different molecular subtypes [2]
Immune evasion can occur through a variety of mechanisms, including manipulation of key immune checkpoints that regulate the adaptive immune system, including cytotoxic lymphocyte antigen 4 (CTLA-4), programmed cell death protein 1 (PD-1), and programmed cell death 1 ligand 1 (PD-L1). e CTLA-4 inhibitor was the first immune checkpoint inhibitor (ICI) to demonstrate a benefit in melanoma; subsequently, response rates for PD-1/PD-L1 inhibitors varied from 10% to 27% for multiple cancers [6,7,8]
Summary
Breast cancer (BC) is the most commonly diagnosed cancer in women worldwide. e challenge in managing this heterogeneous malignancy is that BC is highly aggressive and is always associated with chemical resistance, radiation resistance, hormone therapy resistance, and targeted therapy resistance. erefore, there is an urgent need to find effective drugs to treat BC. In vivo experiments demonstrated the effect of the TM and immunotherapy drug (anti-PD1/anti-TIGIT) combination on BC tumor growth in mice. TM significantly inhibited the proliferation, invasion, and migration of BC cells, and the higher the concentration, the better the inhibition effect. E downregulation of HTR4 was correlated with clinicopathological data and positively correlated with BC prognosis. In vitro experiments showed that TM, anti-PD1, and anti-TIGIT could all inhibit the growth and weight of BC tumors as compared with the control group. When anti-PD1 or anti-TIGIT was used simultaneously with TM, the inhibition of tumors significantly exceeded that in the control group. The combination of anti-TIGIT and TM has the best inhibitory effect. TM inhibited the progression of breast cancer, and its combination with anti-TIGIT could effectively inhibit tumor growth and improve the sensitivity of immunotherapy in breast cancer
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
