Inhibition of MCCC2 Impedes TNBC Progression by Downregulating Leucine Metabolism-Dependent mTOR Signaling

Methylcrotonoyl-CoA carboxylase 2 (MCCC2) has been linked to the progression of multiple tumors, whereas the mTOR has a well-documented role in TNBC. However, the contribution of MCCC2 to TNBC progression and its potential regulation of mTOR signaling remains unclear. This study seeks to assess the functional effect of MCCC2 silencing and tumorigenesis of TNBC, and to investigate whether these effects are mediated through modulation of the mTOR signaling pathway in a leucine-dependent manner.

The GEPIA database was utilized to assess MCCC2 expression and its prognostic significance in breast cancer. Functional assays were employed to evaluate the biological effects of MCCC2 knockdown. The CPTAC database was used to explore MCCC2-associated signaling pathways. The involvement of the mTOR pathway was further examined by combining MCCC2 knockdown with rapamycin treatment and leucine-deprivation experiments.

MCCC2 expression was significantly elevated in breast cancer tissues and associated with poor prognosis. Knockdown of MCCC2 in TNBC cells inhibited proliferation, migration, invasion, and tumor growth. Bioinformatic analyses revealed a strong association between MCCC2 and several oncogenic pathways, including mTOR, MYC/MYCN, NRF2, and RTK. Notably, the inhibitory effects of MCCC2 knockdown were reversed by rapamycin and abolished under leucine-free culture conditions, suggesting a leucine-dependent mechanism of mTOR regulation.

MCCC2 promotes TNBC progression by activating the mTOR signaling pathway in a leucine-dependent manner. Targeting MCCC2 and its metabolic axis may represent a promising therapeutic strategy for TNBC.