Estrogen receptor-associated expression of keratinocyte growth factor and its possible role in the inhibition of apoptosis in human breast cancer.

Although estrogen is known to play a crucial role in the pathogenesis of breast cancer, the molecularmechanisms underlying the action of estrogen remain elusive. In the present study, we focused on keratinocytegrowth factor (KGF) and its receptor (KGFR) in the pathogenesis of breast cancer, as a growth factor mediatingestrogen action, since significant roles of KGF were demonstrated in various steroid hormone-dependenttissues. First, using paraffin-embedded specimens from 42 breast cancer patients, we examined expressionpatterns of KGF and KGFR by both immunohistochemistry using newly generated antibodies andnonradioactive in situ hybridization with T–T dimerized synthetic oligonucleotide probes. We next comparedthe results with the expression of estrogen receptor (ER) a and b, proliferative activity and apoptotic frequency(TUNEL staining). Also, the similar approaches were taken to analyze the expression and role of KGF in ERpositive(MCF7, ZR-75-1) and ER-negative (SK-BR-3, MDA-MB-231) human breast cancer cell lines in vitro. In thesurgical specimens, KGF was expressed in cancer cells as well as stromal cells in 19/42 cases (45%), whileKGFR was found in cancer cells in 24/42 cases (57%). The distribution of protein and mRNA in the analysis ofboth KGF and KGFR expression generally coincided. Moreover, KGF expression was closely associated withthe expression of ER a, and the coexpression of KGF and KGFR significantly correlated with lower TUNELindex, but not with proliferative activity. In accordance with the in vivo findings, KGF expression was detectedonly in ER a-positive MCF7 and ZR-75-1 cells in vitro. And more importantly, we found the inhibitory effect ofKGF upon the induction of apoptosis by anticancer drugs in MCF7 cells. Collectively, our results indicate thatER a may be involved in KGF expression, and that KGF may play antiapoptotic roles, rather than mitogenic, inhuman breast cancer.