Absence of stromal caveolin-1 is an important stressor in spontaneous mammary tumors driven by Her-2/neu

CUELLO CARRION F. D.; CAYADO-GUTIÉRREZ N.; NATOLI A.; RESTALL C.; ANDERSON R. L.; CIOCCA D. R.

Porto Alegre

Workshop; IX Cell Stress Society International Workshop on the Molecular Biology of Stress Responses; 2012

Cell Stress Society International

Introduction: Caveolin-1 (Cav-1) interacts with and regulates several receptors and signalling molecules functioning in lipid homeostasis and transport. In a recent study we found that Cav-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some breast cancers. No association between Cav-1 expression in the epithelial compartment and clinical outcome was detected. However, high levels of Cav-1 in the stromal tissue surrounding the tumor associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her-2/neu overexpression was accelerated in mice lacking Cav-1 suggesting that the presence of Cav-1 in the tumor microenvironment regulates the rate of tumor development. Objectives: To examine whether the loss of stromal Cav-1 can cause a stressful environment that modulates the expression of heat shock proteins (HSPs) and other important molecules in the tumor. Methodology: Mammary tumors derived from wild type or Cav-1 null mice transgenic for the MMTV-neu oncogene were examined by immunohistochemistry. The mammary tumors were ER and ER negative. We also evaluated Her-2/neu and other important molecules, including HSPs, PTEN, beta-catenin, MTA1 in Cav-1 +/+ (n=8) and Cav-1 -/- (n=7) animals. Results: A drastic reduction in the extent of apoptosis was observed in the tumors from mice lacking Cav-1. Bcl-2 was not detected in the tumors and Bax and survivin were not differentially expressed. In contrast, HSPA (Hsp70 detected by mouse MAb BRM22) tumor levels were almost double in the Cav-1 -/- animals. On the other hand, HSPB1 (Hsp25/27) tumor levels were significantly lower in the Cav-1 -/- mice. The tumors from mice lacking of Cav-1 showed higher HSPC4 (Gp96 or Grp94), but no differences in HSPC1 (Hsp90), HSPA5 (Grp78) or HSPD1 (Hsp60). PTEN nuclear levels were significantly higher in tumors arising in the Cav-1 null mice while p-Akt levels did not change significantly. MTA1 and beta-catenin levels were not changed. In all cases beta-catenin was localised to the cell membrane. In comparison, in Her-2/neu positive human breast cancer, exclusive beta-catenin localisation was associated with enhanced disease free survival. Conclusions: The presence of Cav-1 in the tumor microenvironment modulates the response of specific HSPs, PTEN and tumor development.