α-Parvin promotes breast cancer progression and metastasis through interaction with G3BP2 and regulation of TWIST1 signaling

Identification of molecular alterations driving breast cancer progression is critical for the development of effective therapy. In this study, we show that the level of alpha-parvin is elevated in triple-negative breast cancer cells. The depletion of alpha-parvin from triple-negative breast cancer cells effectively inhibits breast cancer cell growth, migration, and invasion in vitro, and tumor progression and metastasis in vivo. At the molecular level, we identify Ras-GTPase-activing protein SH3-domain-binding protein 2 (G3BP2) as an alpha-parvin-binding protein. Knockdown of alpha-parvin promotes G3BP2 interaction with TWIST1, increases ubiquitination and proteasome-dependent degradation of TWIST1, and consequently reduces the cellular level of TWIST1 and its downstream signaling. Importantly, the depletion of G3BP2 reverses the reduction in the level and signaling of TWIST1 and the suppression of breast cancer progression induced by the loss of alpha-parvin. Furthermore, the reexpression of an alpha-parvin mutant in which the G3BP2-binding site is ablated, unlike that of wild-type alpha-parvin, in alpha-parvin-deficient breast cancer cells, is unable to restore the level and signaling of TWIST1 and promote breast cancer progression. Finally, we show that protein level of alpha-parvin is highly positively correlated with that of TWIST1 in human triple-negative breast cancer patients. Our studies reveal a novel signaling pathway consisting of alpha-parvin, G3BP2, and TWIST1 that regulates breast cancer progression and metastasis, and suggest that the activation of this signaling pathway is a key factor for driving the progression and poor clinical outcome of human ER-negative breast cancer.