Keratinocyte growth factor (KGF) induces aromatase activity in cultured MCF-7 human breast cancer cells

Abstract

Estrogen is the major hormonal stimulus for growth of the hormonal-dependent type of breast cancer. The rate-limiting step in the conversion of androgens to estrogens in breast tumors is catalyzed by aromatase, one of a series of related P-450 enzymes involved in the production of steroid hormones. An interesting correlation has been found between KGF mRNA and aromatase mRNA expression in human breast tumors. Tumors that express aromatase mRNA exhibit strong KGF expression, while tumors that do not express aromatase are weak or negative for KGF expression. Thus, it is reasonable to theorize that a possible association between KGF and aromatase in controlling human breast tumor growth exists. The purpose of the current study was to establish whether there is any interaction between KGF, which is known to have epithelial-specific mitogenic activity on breast cancer cells in vitro, and the synthesis of estradiol within the hormone-dependent breast cancer epithelial cells. In the present study, we have demonstrated that KGF stimulates aromatase activity in human breast cancer cells (MCF-7) in a dose-dependent manner. Our data shows that recombinant human KGF, at a dose as low as 10 ng/ml, can significantly increase aromatase activity 2-fold over controls. In agreement with this observation, we also found that aromatase mRNA levels were increased after 10 ng/ml KGF treatment in MCF-7 cells. These results indicate that the stimulatory effect of KGF on aromatase activity may be mediated by alterations in aromatase mRNA levels or in the efficiency of the translation of the message in MCF-7 cells. In addition, our results have demonstrated that modulation of aromatase activity appears to correlate with the stimulation of proliferative activity by KGF in MCF-7 cells. These results are consistent with our previous observations that estradiol-17 beta stimulates KGF expression in human breast cancer stromal cells, leading to the speculation that breast malignant transformation is associated with a positive feedback stimulation, whereby estradiol-17 beta stimulates breast cancer stromal cell production of KGF, and KGF subsequently stimulates aromatase activity in breast cancer cells, consequently raising levels of estradiol-17 beta, in turn acts on breast stromal cells to yield more KGF. Such a positive feedback loop could play an important role in the loss of growth control in human breast cancer cells.