Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression

Adipokines (leptin, adiponectin, and hepatocyte growth factor (HGF)) secreted from adipose tissue have come to be recognized for their contribution to the mechanisms by which obesity and related metabolic disorders influence breast cancer risk. In this review, we discuss the direct and indirect effects of these protein factors on the biological and clinical aspects of breast cancer biology, and emphasize their distinctive modes of action through endocrine-, paracrine-, and autocrine-mediated pathways. The stimulatory effects of leptin on breast cancer growth were considered to occur primarily via activation of the estrogen receptor; however, new evidence suggests that leptin may be acting on downstream cell signaling pathways in both estrogen-dependent and -independent cell types. Another secretory adipokine, HGF, may act largely not only to promote tumor cell invasion, but also to enhance tumor growth indirectly by stimulating angiogenesis. In contrast, adiponectin, an endogenous insulin sensitizer, exerts a direct growth-inhibitory effect on tumor cells by downregulating cell proliferation and upregulating apoptosis, and also inhibits tumor-related angiogenesis.