Comparative study on the functions of LDHA and LDHC in triple-negative breast cancer.

[BACKGROUND] Lactate dehydrogenase (LDH) is a key enzyme in the aerobic glycolysis pathway (Warburg effect) of tumors. Triple-negative breast cancer (TNBC), a subtype of breast cancer, is characterized by elevated levels of the LDHA isoenzyme. However, related research is limited, and whether the functions of LDH isoenzymes differ in TNBC remains unclear. Therefore, this study aimed to investigate the functional similarities and differences between LDHA and LDHC in TNBC progression.

[METHODS] This study first analyzed the expression levels of LDHA and LDHC in the TCGA-BRCA database via bioinformatics. Lentiviral vectors were used to overexpress or knock down LDHA and LDHC expression. Their effects on TNBC cell proliferation, migration, invasion, and cell cycle were assessed using colony formation assays, MTT assays, Transwell assays, wound healing assays, and flow cytometry. A mouse xenograft tumor model was established to investigate the impact of LDHA and LDHC on TNBC progression in vivo. Western blotting was used to detect changes in key proteins of the PI3K/AKT/mTOR signaling pathway and epithelial-mesenchymal transition (EMT) to preliminarily reveal the underlying mechanisms.

[RESULTS] Analysis of the TCGA-BRCA database showed upregulated expression of both LDHA and LDHC in TNBC samples. In vitro experiments demonstrated that overexpression of either LDHA or LDHC promoted the proliferation, invasion, and migration of MDA-MB-231 cells, with the promoting effect of LDHC being significantly stronger than that of LDHA. Knockdown of LDHA or LDHC inhibited the proliferation, invasion, and migration of MDA-MB-231 cells, and the inhibitory effect of LDHC knockdown on cell proliferation and invasion was stronger than that of LDHA knockdown. Intriguingly, knockdown of LDHC, but not LDHA, induced G1 phase arrest in MDA-MB-231 cells. In vivo experiments showed that overexpression of both LDHA and LDHC promoted the growth of subcutaneous xenograft tumors in mice, with the effect of LDHC being significantly stronger than that of LDHA. Western blot results indicated that overexpression of LDHA and LDHC significantly increased PI3K protein levels and elevated the p-AKT/AKT and p-mTOR/mTOR ratios, whereas their knockdown produced the opposite results. Furthermore, overexpression of LDHA and LDHC led to downregulation of E-cadherin and upregulation of N-cadherin and other related proteins, while knockdown of LDHA and LDHC resulted in the opposite effects.

[CONCLUSION] Overexpression of both LDHA and LDHC promotes the proliferation, invasion, and migration of MDA-MB-231 cells, with the effect of LDHC overexpression being more pronounced than that of LDHA. Both LDHA and LDHC can regulate the PI3K/AKT/mTOR signaling pathway and the EMT process, which may represent their molecular mechanisms in promoting cancer.