Because TGF-β signaling elicits both pro-proliferative and tumor-suppressive responses depending on the biological context [40], we addressed the specific impact of TGF-β dysregulation in HNSCC in cell lines harboring SMAD4 alterations (CAL27, CAL33 and UM-SCC-2), using non-tumorigenic, spontaneously immortalized normal oral keratinocytes (NOKSI) and a SMAD4 wild type containing HNSCC line (BHY) as controls. The gene discussed is SMAD4; the disease is head and neck squamous cell carcinoma.