The hedgehog signaling network, mammary stem cells, and breast cancer: connections and controversies.

Several signal transduction networks have been implicated in the regulation of mammary epithelial stem cell self-renewal and maintenance (Kalirai and Clarke 2006; Liu et al. 2005). These signaling networks include those of the Wnt, Notch, TGFO, EGF, FGF, IGF, and most recently, the Hedgehog (Hh) families of secreted ligands. However, we currently know very little about the cellular and molecular mechanisms by which these signaling pathways function to regulate normal epithelial stem/progenitor cells. What is clear is that the regulatory signaling networks thought to control normal stem/progenitor cell self-renewal and maintenance are, with the current sole exception of the hedgehog network, well-documented to have contributory roles in mammary cancer development and disease progression when misregulated. In this review, genetic regulation of mammary gland development by hedgehog network genes is outlined, highlighting a developing controversy as to whether activated hedgehog signaling regulates normal regenerative mammary epithelial stem cells or, indeed, whether activated hedgehog signaling functions at all in ductal development. In addition, the question of whether inappropriate hedgehog network activation influences breast cancer development is addressed, with emphasis on the prospects for using hedgehog signaling antagonists clinically for breast cancer treatment or prevention.