The upper aerodigestive tract mucosa of patients who develop squamous cell carcinoma of the head and neck (SCCHN) is predisposed to abnormally regulated growth, evidenced by the high incidence of synchronous and metachronous malignancies. We conducted a series of experiments to show that aberrant regulation of the epithelial growth factor, transforming growth factor alpha (TGF-alpha) and its cell surface receptor, the epidermal growth factor receptor (EGFR), contribute to this predisposition. Using molecular biological techniques, we compared the incidence and mechanism of TGF-alpha and EGFR over-production in fresh tumors and histologically normal mucosal specimens from patients with SCCHN and normal, control patients without cancer. In patients with SCCHN, TGF-alpha and EGFR mRNA levels were significantly elevated in both tumor and normal mucosal specimens as compared to levels in control mucosa from non-cancer patients. Neither an enhancement of message stability nor an increase in gene copy number alone accounted for the elevation of EGFR mRNA. Increased production of TGF-alpha and EGFR mRNAs in the histologically "normal" mucosa of patients at risk for a primary or secondary head and neck cancer may serve both as a marker for malignant transformation and as a target for chemoprevention.