Triple-negative breast cancers (TNBCs) are defined by a lack of expression of 
estrogen, progesterone, and HER2 receptors. Because of the absence of identified 
targets and targeted therapies, and due to a heterogeneous molecular 
presentation, treatment guidelines for patients with TNBC include only 
conventional chemotherapy. Such treatment, while effective for some, leaves 
others with high rates of early relapse and is not curative for any patient with 
metastatic disease. Here, we demonstrate that these tumors are sensitive to the 
heat shock protein 90 (Hsp90) inhibitor PU-H71. Potent and durable anti-tumor 
effects in TNBC xenografts, including complete response and tumor regression, 
without toxicity to the host are achieved with this agent. Notably, TNBC tumors 
respond to retreatment with PU-H71 for several cycles extending for over 5 
months without evidence of resistance or toxicity. Through a proteomics 
approach, we show that multiple oncoproteins involved in tumor proliferation, 
survival, and invasive potential are in complex with PU-H71-bound Hsp90 in TNBC. 
PU-H71 induces efficient and sustained downregulation and inactivation, both in 
vitro and in vivo, of these proteins. Among them, we identify downregulation of 
components of the Ras/Raf/MAPK pathway and G(2)-M phase to contribute to its 
anti-proliferative effect, degradation of activated Akt and Bcl-xL to induce 
apoptosis, and inhibition of activated NF-kappaB, Akt, ERK2, Tyk2, and PKC to 
reduce TNBC invasive potential. The results identify Hsp90 as a critical and 
multimodal target in this most difficult to treat breast cancer subtype and 
support the use of the Hsp90 inhibitor PU-H71 for clinical trials involving 
patients with TNBC.