P-cadherin and beta-catenin are useful prognostic markers in breast cancer patients; beta-catenin interacts with heat shock protein Hsp27.
The cadherin-catenin proteins have in common with heat shock proteins (HSP) the capacity to bind/interact proteins of other classes. Moreover, there are common molecular pathways that connect the HSP response and the cadherin-catenin protein system. In the present study, we have explored whether in breast cancer the HSP might interact functionally with the cadherin-catenin cell adhesion system. Beta-catenin was immunoprecipitated from breast cancer biopsy samples, and the protein complexes isolated in this way were probed with antibodies against HSP family members. We are thus the first to demonstrate a specific interaction between beta-catenin and Hsp27. However, beta-catenin did not bind Hsp60, Hsp70, Hsp90, gp96, or the endoplasmic reticulum stress response protein CHOP. To confirm the finding of Hsp27-beta-catenin interaction, the 27-kDa immunoprecipitated band was excised from one-dimensional polyacrylamide gel electrophoresis gels and submitted to liquid chromatography-tandem mass spectrometry with electrospray ionization, confirming a role for Hsp27. In addition, beta-catenin interacted with other proteins including heat shock transcription factor 1, P-cadherin, and caveolin-1. In human breast cancer biopsy samples, beta-catenin was coexpressed in the same tumor areas and in the same tumor cells that expressed Hsp27. However, this coexpression was strong when beta-catenin was present in the cytoplasm of the tumor cells and not when beta-catenin was expressed at the cell surface only. Furthermore, murine breast cancer cells transfected with hsp25 showed a redistribution of beta-catenin from the cell membrane to the cytoplasm. When the prognostic significance of cadherin-catenin expression was examined by immunohistochemistry in breast cancer patients (n = 215, follow-up = >10 years), we found that the disease-free survival and overall survival were significantly shorter for patients expressing P-cadherin and for patients showing expression of beta-catenin in the cytoplasm only (not at the cell surface). The interactions of beta-catenin with Hsp27 and with HSF1 may explain some of the molecular pathways that influence tumor cell survival and the clinical significance in the prognosis of the breast cancer patients.
Fanelli
Mariel A
MA
Oncology Laboratory, Institute of Experimental Medicine and Biology of Cuyo, Regional Center for Scientific and Technological Research, National Research Council (CONICET), Mendoza, Argentina. mfanelli@lab.cricyt.edu.ar
Montt-Guevara
Magdalena
M
Diblasi
Angela M
AM
Gago
Francisco E
FE
Tello
Olga
O
Cuello-Carrión
F Darío
FD
Callegari
Eduardo
E
Bausero
Maria A
MA
Ciocca
Daniel R
DR
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001706:Biopsy; D001943:Breast Neoplasms / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D015820:Cadherins / Q000032:analysis*; D002277:Carcinoma / Q000737:chemistry* / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor / Q000378:metabolism; D018572:Disease-Free Survival; D005260:Female; D055551:HSP27 Heat-Shock Proteins / Q000032:analysis* / Q000378:metabolism; D006360:Heat-Shock Proteins; D006801:Humans; D053208:Kaplan-Meier Estimate; D008325:Mammary Neoplasms, Experimental / Q000473:pathology; D051379:Mice; D008875:Middle Aged; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000032:analysis* / Q000378:metabolism; D011379:Prognosis; D025941:Protein Interaction Mapping; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis; D051176:beta Catenin / Q000032:analysis* / Q000378:metabolism
D015820:Cadherins; D055551:HSP27 Heat-Shock Proteins; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C495270:CTNNB1 protein, human; C057725:HSPB1 protein, human