Upon MTDH modulation in SK-BR-3 and trastuzumab-resistant SK-BR-3/R cells, we confirmed that MTDH overexpression first activated NFκB signal and then influenced PTEN expression, thus maintaining PI3K/Akt signaling pathway in HER2 positive breast cancer, which conferred a survival advantage under trastuzumab exposure. The gene discussed is MTDH; the disease is breast cancer.