Breast Cancer MDA-MB-231 Cells Use Secreted Heat Shock Protein-90alpha (Hsp90α) to Survive a Hostile Hypoxic Environment

Rapidly growing tumours in vivo often outgrow their surrounding available blood supply, subjecting themselves to a severely hypoxic microenvironment. Understanding how tumour cells adapt themselves to survive hypoxia may help to develop new treatments of the tumours. Given the limited blood perfusion to the enlarging tumour, whatever factor(s) that allows the tumour cells to survive likely comes from the tumour cells themselves or its associated stromal cells. In this report, we show that HIF-1 alpha-overexpressing breast cancer cells, MDA-MB-231, secrete heat shock protein-90alpha (Hsp90 alpha) and use it to survive under hypoxia. Depletion of Hsp90 alpha secretion from the tumour cells was permissive to cytotoxicity by hypoxia, whereas supplementation of Hsp90 alpha-knockout tumour cells with recombinant Hsp90 alpha, but not Hsp90 beta, protein prevented hypoxia-induced cell death via an autocrine mechanism through the LDL receptor-related protein-1 (LRP1) receptor. Finally, direct inhibition of the secreted Hsp90 alpha with monoclonal antibody, 1G6-D7, enhanced tumour cell death under hypoxia. Therefore, secreted Hsp90 alpha is a novel survival factor for certain tumours under hypoxia.