Abstract
The Hsp90 family of molecular chaperones includes the cytosolic isoforms Hsp90a and Hsp90β and the mitochondrial isoform Trap1. Hsp90a/βsupport a large number of client proteins in the cytoplasm and the nucleus whereas Trap1 regulates oxidative phosphorylation in mitochondria. Many of the associated proteins and cellular processes are relevant to cancer, and there is ample pharmacological and genetic evidence to support the idea that Hsp90a/βand Trap1 are required for tumorigenesis. However, a direct and comparative genetic test in a mouse cancer model has not been done. Here we report the effects of deleting the Hsp90a or Trap1 genes in a mouse model of breast cancer. Neither Hsp90a nor Trap1 are absolutely required for mammary tumor initiation, growth and metastasis induced by the polyoma middle T-antigen as oncogene. However, they do modulate growth and lung metastasis in vivo and cell proliferation, migration and invasion of isolated primary carcinoma cells in vitro. Without Hsp90a, tumor burden and metastasis are reduced, correlating with impaired proliferation, migration and invasion of cells in culture. Without Trap1, the appearance of tumors is initially delayed, and isolated cells are affected similarly to those without Hsp90a. Analysis of expression data of human breast cancers supports the conclusion that this is a valid mouse model highlighting the importance of these molecular chaperones.
Highlights
Members of the Heat shock protein 90 (Hsp90) family of molecular chaperones are highly conserved, ubiquitous and abundant ATP-dependent proteins with different isoforms that share a high degree of sequence identity and can be found in several cellular compartments: Hsp90α and Hsp90β in the cytoplasm and the nucleus, here referred to generically as Hsp90, Trap1 in mitochondria, Grp94 in the endoplasmic reticulum, and Hsp90C in chloroplasts [1]
Our question was whether there was any change in the protein levels of Hsp90α and Trap1 in metastases compared to the primary tumors and to normal lung (Figure 1D and Supplementary Figure 1A and B)
We aimed to address the issue of Hsp90α and Trap1 involvement in breast cancer initiation, progression and metastasis by using an in vivo mouse breast cancer model
Summary
Members of the Heat shock protein 90 (Hsp90) family of molecular chaperones are highly conserved, ubiquitous and abundant ATP-dependent proteins with different isoforms that share a high degree of sequence identity and can be found in several cellular compartments: Hsp90α and Hsp90β in the cytoplasm and the nucleus, here referred to generically as Hsp, Trap in mitochondria, Grp in the endoplasmic reticulum, and Hsp90C in chloroplasts [1]. The cytosolic Hsp is a key component of an ensemble of complexes with a variety of co-chaperones [2], which acts on a wide range of protein substrates called clients Hsp was found to interact with a number of proteins important for breast cancer, for example the hypoxia inducible factor HIF-1α, estrogen receptor α, anti-apoptotic kinase Akt, tumor suppressor protein p53, and the ErbB receptor tyrosine kinase (see https://www.picard.ch/ downloads/Hsp90facts.pdf for a comprehensive overview and references). Some studies have shown that the overexpression of Hsp90β in breast cancer, as part of a set of proteins involved in regulating estrogen receptor α activity, correlates with adverse clinical outcomes [10]; a variety of Hsp inhibitors are in clinical trials for breast cancer treatment [11], further highlighting the potential of Hsp as a therapeutic target
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
