Depletion or inhibition of TPM3 impaired cell morphology, motility, and invasion in hypoxic triple-negative breast cancer cells, and synergized with Paclitaxel and Doxorubicin.
Does TPM3 depletion or inhibition reduce hypoxia-mediated motility and invasion in TNBC cells?
TPM3 is a hypoxia-inducible, HIF-1-regulated effector that promotes TNBC cell motility and invasion, and its inhibition synergizes with standard chemotherapy.
Abstract Hypoxia is a defining feature of triple-negative breast cancer (TNBC), driving invasion, metastasis, and therapy resistance. Understanding the molecular effectors of hypoxia is essential to identify new therapeutic targets. Here, we investigated tropomyosin 3 (TPM3), an actin-binding protein that regulates filament stability. TPM3 is significantly upregulated in breast cancer, including in TNBC, where elevated levels correlate with poor overall survival. Using validated hypoxia signatures and TNBC cell models, we show that TPM3 is induced in physiologically relevant hypoxic conditions in a HIF-1–dependent manner. Both mRNA and protein levels of TPM3 increased in response to hypoxia, and TPM3 colocalised with F-actin, supporting cytoskeletal organisation. Functional assays demonstrated that depletion or inhibition of TPM3 impaired cell morphology, motility, and invasion in hypoxic TNBC cells, while not affecting viability. Notably, TPM3 inhibition synergised with Paclitaxel and Doxorubicin, enhancing therapeutic efficacy. In addition, TPM3 was incorporated into extracellular vesicles (EVs), with hypoxia increasing EV-mediated transfer of TPM3 to normoxic cells and promoting their motility. These findings establish TPM3 as a hypoxia-inducible, HIF-1–regulated effector of cytoskeletal dynamics and intercellular communication, underscoring its potential as a therapeutic target to limit TNBC aggressiveness and improve treatment outcomes.
Zhou et al. (Sat,) conducted a other in Triple-negative breast cancer. TPM3 inhibition (ATM-3507) or depletion (siRNA) vs. Control was evaluated on Cell motility and invasion. Depletion or inhibition of TPM3 impaired cell morphology, motility, and invasion in hypoxic triple-negative breast cancer cells, and synergized with Paclitaxel and Doxorubicin.