Absence of stromal caveolin-1 alters heat shock protein expression in spontaneous mammary tumors driven by Her2/neu expression in caveolin-1null mice

CIOCCA D. R.; CUELLO CARRIÓN F. D.; RESTALL C.; ANDERSON R. L.

Cambridge, MA, USA.

Workshop; Workshop on Extracellular Chaperones and their Plasma Antibodies; 2010

Cell Stress Society International

Caveolae are specialized lipid rafts containing caveolin-1 (cav-1) that interact with and regulate several receptors and signalling molecules. Cav-1 is also present in the cytosol, functioning in lipid homeostasis and transport. In a recent study we assessed cav-1 levels in normal breast tissue and breast cancer. We found that cav-1 was not expressed in normal breast luminal epithelium but was present in the epithelial compartment of some tumors. The study revealed no association between cav-1 expression in the epithelial compartment and clinical outcome. However, high levels of cav-1 in the stromal tissue surrounding the tumor, rather than within tumor cells, associated strongly with reduced metastasis and improved survival. Using an animal model, we found that the onset of mammary tumors driven by Her2/neu expression was accelerated in mice lacking cav-1 (Am J Pathol 174:2035, 2009). In addition, immunoprecipitation studies using human breast cancer tissues showed that beta-catenin interacted with HSPB1 (hsp27) and cav-1 (Cell Stress & Chaperones 13:207, 2008). With these supporting data we studied the heat shock protein response in mice lacking stromal cav-l. These mice had mammary-specific expression of Her-2/neu and were bred from cav-1 null mice and from mice transgenic for the MMTV-neu oncogene. In all cases the tumors arising were estrogen receptor alpha and beta negative, and the expression levels of Her2/neu evaluated by immunohistochemistry did not show differences between the cav-1 +/+ (n=8) and the cav-1-/- (n=7) animals. However, a drastic reduction in the amount of apoptosis was observed in breast tumors from animals lacking cav-1. Bcl-2 was not detected in the tumors and the expression levels of Bax and survivin were not different. In contrast, HSPA (hsp70 detected by mouse MAb BRM22) tumor levels were almost double in the cav-1 -/- animals. On the other hand, HSPB1 tumors levels were significantly lower in the cav-1 -/- mice. The breast tumors from mice lacking of cav-1 showed higher HSPC4 (gp96 or grp94), but no differences in HSPC1 (hsp90), HSPA5 (grp78), HSPD1 (hsp60) were observed. These results show that the presence of cav-1 in the tumor microenvironment modulates the response of specific heat shock proteins as well as tumor development.