TMEM45A promote triple-negative breast cancer (TNBC) related depression via the AKT/mTOR signaling pathway

Patients diagnosed with triple-negative breast cancer (TNBC) frequently experience depression, a comorbidity that substantially compromises quality of life and survival outcomes. This study aimed to characterize the functional role and underlying regulatory mechanisms of TMEM45A in triple-negative BC related depression (TN-BCRD). First, we validated the regulatory effects of TMEM45A in 4T1 cells. An in vitro TN-BCRD model was established using HT22 hippocampal neurons co-exposed to 4T1 cell-derived conditioned medium and corticosterone. The siRNA of TMEM45A was transfected into 4T1 cells to investigate the effect of tumor cell-expressed TMEM45A on the TN-BCRD phenotype and the AKT/mTOR signaling pathway. For in vivo validation, we established 4T1 tumor-bearing mice model and examined the effects of tumoral TMEM45A on tumor growth, depression-like phenotypes, and hippocampal AKT/mTOR signaling. TMEM45A is significantly overexpressed in TNBC tissues. Knockdown of TMEM45A induced apoptosis and inhibited migration and invasion in 4T1 cells, while it promoted proliferation and reduced apoptosis in HT22 cells. TMEM45A knockdown also attenuated the activity of AKT/mTOR signaling and reduced the secretion of pro-inflammatory factors in HT22 cells under BCRD conditions. In vivo mice experiments demonstrated that TMEM45A knockdown in 4T1 cells suppressed the tumor growth and rescued depression-like behaviors in tumor-bearing mice. TMEM45A serves as a key regulator of TN-BCRD, and its targeted inhibition may represent a promising therapeutic strategy for this condition.