AREG and neoplasm: For example, (ADAMTS1) and matrix metalloproteinase-1 (MMP1) participate in a paracrine signaling cascade that includes the release of metastasis membrane-bound epidermal-growth-factor (EGF-) like growth factors, amphiregulin (AREG), heparin-binding EGF (HB-EGF), and transforming growth factor alpha (TGF alpha) from tumor cells resulting in a downregulation of osteoprotegerin expression in osteoblasts and therefore modulating brain microenvironment in favor of osteoclastogenesis and bone metastasis [74].