Enhancement of vascular endothelial growth factor release in long-term drug-treated breast cancer via transient receptor potential channel 5-Ca2+-hypoxia-inducible factor 1α pathway

Chemotherapy targeting anti-angiogenesis in tumors may have insufficient efficacy, but little is known about the underlying mechanisms. Here, we showed that the Ca2+-permeable channel, TrpC5, is highly expressed in human breast cancer after long-term chemotherapy drug-treatment. It mediates downstream hypoxia-inducible factor 1 alpha accumulation in the nucleus, and then activates the transcription of vascular endothelial growth factor which promotes tumor angiogenesis, leading to a poor chemotherapeutic outcome. We verified this mechanism at both the cellular and xenograft levels. Moreover, in samples from patients, high TrpC5 expression was correlated with enhanced tumor vasculature after chemotherapy. Taken together, our research demonstrated the essential role of TrpC5 in tumor angiogenesis when facing the challenge of chemotherapy and presents a new potential target for overcoming the high vasculature of human breast cancer after chemotherapy. (C) 2015 Elsevier Ltd. All rights reserved.