Mechanisms of egfr Gene Transcription Modulation: Relationship to Cancer Risk and Therapy Response

• Published in: Clinical cancer research 2006-12, Vol.12 (24), p.7252-7260
• Main Authors: Brandt, Burkhard, Meyer-Staeckling, Sönke, Schmidt, Hartmut, Agelopoulos, Konstantin, Buerger, Horst
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Biological and medical sciences; Breast Neoplasms - etiology; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; CA repeats; cancer risk; Carcinoma - etiology; Carcinoma - genetics; Carcinoma - metabolism; Diet - adverse effects; egfr; Epidemiology; Female; Gene Amplification; Gene Expression Regulation; Gene Frequency; gene regulation; gene transcription; General aspects; Humans; Medical sciences; Models, Biological; Neoplasms - diagnosis; Neoplasms - epidemiology; Neoplasms - therapy; Pharmacology. Drug treatments; Polymorphism, Genetic; Prognosis; Public health. Hygiene; Public health. Hygiene-occupational medicine; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; Regulatory Sequences, Nucleic Acid; Risk; Tandem Repeat Sequences - physiology; therapy response; Transcription, Genetic - physiology
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-0626

The epidermal growth factor receptor (EGFR) plays a crucial role in growth, differentiation, and motility of normal as well as cancer cells. For predictive cancer diagnostics and therapeutic targeting of EGFR, it is important to know how the expression level of EGFR is controlled and related to receptor signaling. A novel transcriptional regulation mechanism has been described that depends on the length of a CA repeat in intron 1 [CA simple sequence repeat 1 (CA SSR I)] of the EGFR gene. Thereby, the number of CA repeats is inversely correlated to pre-mRNA synthesis. Indirect evidence for the importance of this mechanism includes the preferential occurrence of amplifications in cancer tissue harboring short CA repeats in this sequence and the discovery of distinct alleles in young breast cancer patients with a family history of the disease and in Japanese breast cancer patients. It can be postulated that the length of the CA repeat influences DNA bendability and, in consequence, the binding of repressor proteins. In summary, it seems that the CA SSR I represents an inherited variable for response to anti-EGFR therapies that could be determined before therapy. Moreover, the potential for synergistic effects with other polymorphism [e.g., EGFR R497K (HER-1 497K) and CCND1 A870G] leading to a simultaneous increase of EGFR signaling activity and expression should be investigated. From a practical perspective, assessment of the CA SSR I number of CA dinucleotide repeats as a predictor for clinical outcome is very attractive because it is a constant feature that does not change over time and can be easily measured in normal and cancer tissues (blood cells, skin, and tumor biopsies) in an assay that is technically simple, objective, and even quantitative.