ReviewNew paradigms for the Hedgehog signaling network in mammary gland development and breast Cancer

•Properly regulated Hedgehog network gene function in the mammary epithelium, mammary fat pad stroma, and endocrine organs, is critical for normal mammary ductal morphogenesis and normal proliferation rates.•Upregulated expression of Hedgehog network members, including SHH, SMO, and GLI1, together with reduced PTCH1/2 mRNA and PTCH1 protein expression, is associated with tumorigenesis, invasion/metastasis, and TIC (tumor initiating cell) function•SHH/GLI1 upregulation may be particularly associated with ER + breast tumors.•Data show roles for Hedgehog network members in the neuroendocrine signaling axis, but specific roles with respect to mammary gland development and breast cancer are undefined.

The Hedgehog signaling network regulates organogenesis, cell fate, proliferation, survival, and stem cell self-renewal in many mammalian tissues. Aberrant activation of the Hedgehog signaling network is present in ~ 25% of all cancers, including breast. Altered expression of Hedgehog network genes in the mammary gland can elicit phenotypes at many stages of development. However, synthesizing a cohesive mechanistic model of signaling at different stages of development has been difficult. Emerging data suggest that this difficulty is due, in part, to non-canonical and tissue compartment-specific (i.e., epithelial, versus stromal, versus systemic) functions of Hedgehog network components. With respect to systemic functions, Hedgehog network genes regulate development of endocrine organs that impinge on mammary gland development extrinsically. These new observations offer insight into previously conflicting data, and have bearing on the potential for anti-Hedgehog therapeutics in the treatment of breast cancer.