Study On The Mechanism Underlying Valproic Acid Reversed Trastuzumab Resistance In HER2-positive Breast Cancer Cells

Amplification and/or overexpression of HER2 occur in approximately 25%of invasive breast cancer and are significantly associated with a worse prognosis of breast cancer patients.Trastuzumab,a humanized monoclonal antibody against HER2 receptor,has been successfully used in early-stage and metastatic breast cancer therapy of patients with HER2-overexpressing tumors as monotherapy and in combination with other agents;however,both primary and acquired resistances to trastuzumab are common and currently represent a significant clinical problem.Thus,seeking of novel therapeutic strategies/agents to overcome trastuzumab resistance is vital to improve the survival of breast cancer patients whose tumors overexpress HER2.In our current study,we explored whether valproic acid(VPA),a clinically used anticonvulsant drug with reported HDACi activity,reverses trastuzumab resistance in HER2-positive breast cancer cells.We have found that VPA inhibits proliferation of both trastuzumab-sensitive SKBR3 and BT474 cell lines as well as their corresponding trastuzumab-resistant SKBR3-Pool2 and BT474-HR20 cell lines in a dose-and time-dependent manner,which is accompanied by significant reduction of cyclin D1 as well as induction of P21.Meanwhile,VPA also induces caspase-dependent apoptosis in all aforementioned four cell lines.More interestingly,VPA not only significantly enhances the anti-proliferative effects of trastuzumab,but also potentiates trastuzumab-induced apoptosis in trastuzumab-sensitive and resistant cells.Our further mechanistic studies revealed that VPA treatment results in significant inactivation of PI3K/Akt signaling via simultaneous down-regulation of HER2 and HER3 in HER2-positive breast cancer cancer cells,an effect which could be mainly arrtibuted to induction of HER family members-targeting microRNAs including miR-125a,miR-125b and miR-205 by VPA.Taken together,we presented here that VPA reverses trastuzumab resistance in HER2-positive breast cance cells via downregulation of HER2/HER3 signaling in a miRNAs-inducing-dependent manner.Our study offered not only a preliminary theoretic basis but also experimental data for further use of VPA in combination with trastuzumab in treatment of patients with HER2-positive breast cance.