Abstract: Background and purpose: Glutamate metabotropic receptor 4 (GRM4) is highly expressed in many tumors, and its expression is associated with the prognosis of patients. However, the function of GRM4 in breast cancer is still not clear. This study aimed to investigate the effects of positive allosteric modulators VU0364439 and VU0364770 on the proliferation and apoptosis of breast cancer cells, and then provide novel strategies for breast cancer targeted therapy. Methods: VU0364439 and VU0364770 were added solely or in combination into breast cancer cell lines MDA-MB-231, MCF-7 and SK-BR-3. The proliferation activities of these cells were detected using CellTiter- Glo^® luminescent cell viability assay. Annexin Ⅴ-PI double staining was used to detect the apoptosis of breast cancer cells. The expressions of GRM4 gene in six breast cancer cell lines were detected using real-time fluorescent quantitative polymerase chain reaction (RTFQ-PCR). After VU0364439 and VU0364770 were uesd solely or in combination, the expression of GRM4 gene was detected in the cell line with the highest GRM4 expression. Results: Compared with the control group, the proliferations of breast cancer cells MCF-7, MDA-MB-231 and SK-BR-3 were significantly inhibited after VU0364439 and VU0364770 were added solely or in combination. VU0364439 and VU0364770 also promoted the cell apoptosis of these breast cancer cell lines. The inhibitory effect of VU0364439 and VU0364770 on the proliferation of breast cancer cells was not significantly different when they were used in combination (P>0.05). RTFQ-PCR assay showed that the expression of GRM4 was higher in MCF-7 cells. The GRM4 expression could be activated when VU0364439 and VU0364770 were used solely or in combination. Conclusion: GRM4 positive allosteric modulators could inhibit breast cancer cell proliferation and promote cell apoptosis. This biological effect might function by activating GRM4 expression. This study lays the foundation for exploring the effect of GRM4 in breast cancer and developing novel strategies for breast cancer targeted therapy.

Key words: Glutamate metabotropic receptor 4, Positive allosteric modulators, Breast cancer, Targeted therapy