[Frontiers in Bioscience 11, 1818-1843, May 1, 2006]

Biomolecular markers of breast cancer

Andrea Nicolini 1, Angelo Carpi 2, and Giulio Tarro 3

1 Department of Internal Medicine, 2 Department of Reproduction and Aging, University of Pisa,3 Department of Diagnostics, Division of Virology, D Cotugno Hospital, Naples, Italy

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Tissue markers
3.1. Intracellular receptors (estrogen and progesterone receptors)
3.1.1. The estrogen receptors (ER-alpha, ER-beta)
3.1.1.1. Structure
3.1.1.2. Function
3.1.1.3. Clinical utility
3.1.2. The progesterone receptors (PR-A, PR-B)
3.1.2.1. Structure and function
3.1.2.2. Gene regulation
3.1.2.3. Pathologic and clinical considerations
3.2. HER2/neu (erbB2)
3.2.1. Structure
3.2.2. Function
3.2.3. Clinical utility
3.3 p53, gene and protein
3.3.1. Structure and function
3.3.2. Clinical utility
3.4. Ki-67/MIB-1
3.4.1. Structure and function
3.4.2. Clinical utility
3.5. Vascular endothelial growth factor (VEGF)
3.5.1. Structure and function
3.5.2. Clinical utility
4. Circulating tumor markers
4.1. Tumor associated antigens (TAAs): general aspects
4.1.1. Carcinoembryonic antigen (CEA)
4.1.2. CA15.3
4.1.3. Tissue polypeptide antigen (TPA)
4.1.4. Mucin-like carcinoma associated antigen (MCA)
4.1.5. CA549
4.2. Clinical role of circulating TAAs
4.3. Other circulating markers
4.3.1. HER2/neu
4.3.2. p53 autoantibodies
4.3.3. Cytokeratin-positive cells
4.3.4. Autoantibodies to nucleophosmin (NPM)
4.3.5. Serum soluble vascular cell adhesion molecules: intracellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1) and E-selectin
5. Summary and perspective
6. References

1. ABSTRACT

Here, the structure, function, biological and pathological significance and clinical utility of the principal biomolecular markers of breast cancer is reviewed. Each marker was scored for clinical utility using a recently developed tumor marker utility grading system (TMUGS). Among the tissue markers, ERs and PRs are important prognostic/predictive factors and the only tissue markers routinely determined. ER cross-talks with other growth factors while co-regulatory factors enhance (co-activators) or decrease (co-repressors) its transcriptional activity. C-erbB-2 and Ki67/MIB-1 select for adjuvant chemotherapy a subgroup of lymph-node negative patients at a high risk of relapse. Monoclonal antibodies (trastuzumab, gefitinib, erlotinib and bevacizumab) targeting tissue markers and involved in tumor growth and metastasization (EGFR, C- erbB-2, VEGF) have been developed; they showed therapeutical single agent activity as well as potent synergy with chemotherapy agents in metastatic cancer. Among circulating markers, some are potentially useful in the early detection and monitoring of metastatic disease; nevertheless, none is routinely recommended. To suspect distant metastases, CEA-TPA-CA15.3 panel attained accuracy of about 90%. ECD HER2-neu, p53 and nucleophosmin antibodies seem suitable candidates for different associations. Preliminary observations suggest that an early detection with tumor markers and successive treatment of relapses significantly prolongs disease-free and overall survival in selected patients. In conclusion, biomolecular markers are improving understanding of biology and management of breast cancer.