Keratinocyte Growth Factor as a Survival Factor in Human Breast Cancer

Estrogens are considered to play a central role in human breast carcinogenesis, among the endocrine factors associated with breast cancer. In estrogen-sensitive breast cancer cells, locally and distally produced growth factors engage intracellular signaling pathways and facilitate tumor cell growth. The inappropriate activation of growth factor signaling cascades can promote anti-hormone failure inbreast cancer cells by stimulating cell growth and limiting apoptosis. KGF is a stromal origin growth factor and appears to act specifically on epithelial cells. Our group has shown that KGF stimulates breast cancer cell growth independently without estrogens. However, the mechanisms underlying the regulation of breast cancer by KGF is not well defined. In our study, we found that KGF enhancedbreast cancer cell survival through the down-regulation of ER-α expression. Our results demonstrated that KGF could decrease ER without changing the mRNA expression of progesterone receptor (PR) and pS2. Tamoxifen (Tam) could induce MCF-7 cell death which could be blocked by KGF treatment. KGF alone did not stimulate MCF-7 cell growth. These findings lead to the hypothesis that KGF can promote anti-hormone failure through the regulation of apoptosis and KGF-induced the signaling pathways. Our experiments further proved that that the regulation of ER-α by KGF in MCF-7 cells is via PI3K/Akt pathway. KGF increased Akt phosphorylation and decreased ER mRNA expression which could be blocked by LY294002, a patent inhibitor of Akt pathway. KGF treatment also induced anti-apoptosis via the increase of the Bcl-2 and Bcl-xL proteins and the decrease of the active-form caspase-9 protein whereas LY294002 blocked the KGF-induced effects. KGF maintains the MCF-7 cell survival in the presence of 4OH-Tam. Our data suggested that KGF may function as a potential tumor promoter in regulating the process of tumor growth in human breast. Collectively, these studies provide insight into the role of KGF in the anti-estrogenic resistance of human breast and the underlying signaling pathway in the promotion of human breast carcinomas. The investigations not only further our understanding of human breast cancer biology but also provide rationales for the development of therapeutic approaches targeting KGF/KGFR signaling as a breast cancer treatment.