Elevated Hsp levels in cancer indicate a poor prognosis

CIOCCA D. R.; FANELLI M. A.; CUELLO CARRIÓN F. D.; CASTRO G. N.

Woods Hole, MA, USA

Simposio; IV International Symposium on Heat Shock Proteins in Biology and Medicine; 2008

Cell Stress Society International

Cancer is a very heterogeneous disease, there are more than 200 cancer types and, in a determined tissue/organ, the disease is also very heterogeneous in its behavior. Some cancers are relatively indolent while others are very aggressive and resistant to different treatments. Therefore, researchers are devoting great efforts to characterize the prognosis of the disease and the response to specific treatments. HSP are elevated in many cancer types and since these proteins are in general cytoprotective, the expression of several HSP family members has been analyzed to know whether they are clinically useful to predict the prognosis of the disease, and the significance in anticancer treatments. We have studied these issues mainly by immunopathology in some cancer types. Since cancers are a mixed bag of cells, the results are not uniform to draw a general conclusion however, in several cancer types elevated HSP levels are clearly related with poor prognosis, and sometimes with resistance to chemotherapies. At molecular level there are several clues to understand this association, i.e., the anti-apoptotic role of Hsp70 and Hsp27 (many anticancer treatments kill tumor cells inducing massive apoptosis). In addition, HSPs are able to associate with many other proteins modifying its functional role(s) in cancer biology. In works in collaboration with Dr. Calderwood's laboratory, it has been shown that HSF1 binds to the co-repressor metastasis-associated protein 1 (MTA1) in vitro and in human breast carcinoma samples. The formation of this complex was strongly induced by the transforming ligand heregulin and the complexes incorporated a number of additional proteins including histone deacetylases (HDAC1 and 2) and Mi2alfa, all components of the NuRD co-repressor complex. Such HSF1 complexes participate in repression of estrogen-dependent transcription in breast carcinoma cells treated with heregulin, and this effect was inhibited by MTA1 knockdown. Repression of estrogen-dependent transcription may contribute to the role of HSF1 in cancer. It can also explain the relative poor response to tamoxifen in breast cancer patients co-expressing estrogen/progesterone receptors and Her-2/neu oncoprotein. In recent studies we have examined the association of beta-catenin with Hsp27 and with HSF1 in breast cancer cells and tissue samples. Beta-catenin is an important component of the cadherin-catenin cell adhesion system and in the intracellular signaling pathways. In this study beta-catenin protein expression appeared as an important prognostic factor but depending on its location within the cell compartment. A shorter disease-free survival was found in those patients where beta-catenin was found in the cytoplasm only, not at the cell surface, and in this location (cytoplasm) beta-catenin co-expressed with Hsp27. Murine breast cancer cells transfected with Hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm of the cells. We are now expanding these studies in patients with gliomas.