A 67 KDA NON-HORMONE BINDING ESTRADIOL-RECEPTOR IS PRESENT IN HUMAN MAMMARY CANCERS

The presence of large amounts of a 67 kDa estradiol receptor that does not bind hormone was observed in 8 of 37 human mammary tumors (34 mal ignant and 3 benign). This farm of receptor was detected by its conver sion to hormone binding receptor by an endogenous tyrosine kinase in v itro. All 8 tumors were malignant. In these, the incubation of cytosol with ATP was seen to cause a 1- to 5-fold increase in estradiol-speci fic binding sites. These sites bound estradiol with physiological affi nity, and their appearance was associated with tyrosine phosphorylatio n of estradiol receptor. The enzyme converting the non-hormone binding receptor into the hormone binding receptor is largely present in cyto sol and scarce in membranes. It has been extensively purified. It is a 67 kDa protein under denaturating conditions, binds calmodulin-Sephar ose in a Ca2+-dependent manner, is stimulated by Ca2+ and calmodulin, phosphorylates exogenous actin, is activated by the estradiol-receptor complex. The enzyme interacts with antibodies directed against the ca rboxy-terminal and catalytic domains of c-src. Therefore, it is a puta tive new member of the large c-src-related kinase family. Human mammar y cancers with significant amounts of 67 kDa non-hormone binding recep tor show relatively low levels of hormone binding estradiol receptor. The presence of non-hormone binding receptor that can be activated by in vitro tyrosine phosphorylation suggests that functional interaction of estradiol receptor with tyrosine kinases is altered in malignant t umors and has bearing on loss of hormone dependence and progression of the mammary cancer malignancy. (C) 1996 Wiley-Liss, Inc.