Research Grants Awarded
Prognostic Significance of Soluble EGFR Expression in Breast Cancer
Detection, Diagnosis and Prognosis
Epidermal growth factor receptor (EGFR) and the related HER-2 protein frequently are overexpressed in breast tumors, where high levels of expression of either protein have been correlated with advanced tumor stage, resistance to endocrine therapy, and poor patient prognosis. The importance of this growth factor receptor family in human breast cancer is underscored by the fact that both EGFR and HER-2 are being targeted for novel chemotherapeutic strategies. In addition to full-length EGFR (p170-EGFR), soluble receptor isoforms arise by alternative mRNA splicing and consist of only the EGFR extracellular domain and unique carboxy-terminal peptide sequence. The soluble 110 kDa EGFR isoform (p110-sEGFR) is expressed in many of the same tissues and cells that also express p170-EGFR, including breast cancer tissues. Earlier studies have shown that soluble receptor isoforms can regulate either local growth factor concentrations, or the ligand-dependent activity of their full-length receptor counterparts. Moreover, our recent results indicate that overexpression of p110-sEGFR in human tumors is significantly associated with increased time to disease recurrence, suggesting that p110-sEGFR may inhibit EGFR activity in vivo. While EGFR expression in breast tumors generally is considered to be a poor prognostic indicator, there is disagreement in the literature over its prognostic value and consequently, this marker is not widely used in the clinic. We speculate that earlier studies examining EGFR expression in breast tumors have likely been confounded by co-expression of both p110-sEGFR and p170-EGFR. In this proposal, we will directly test the hypothesis that the ratio of p170-EGFR to p110-sEGFR protein levels in breast cancer tissue will have prognostic value for patients. Specifically, we will first develop a highly sensitive immunohistochemical assay that will distinguish between, and allow for the separate quantitation of, p110-sEGFR and p170-EGFR expression levels in breast tumors in situ; and second, we will use this quantitative assay to objectively measure p110-sEGFR and p170-EGFR expression levels on a tissue microarray containing over 650 primary invasive breast cancers. Statistical analyses will be performed to determine if the expression of either p110-sEGFR or p170-EGFR measured alone, or if the ratio of these two EGFR variants measured together, is associated with several clinical parameters, including patient outcome. The results of this study should lead to a better understanding of the true prognostic significance of EGFR expression in breast cancer. In addition, the results of this pilot study will provide the basis for designing prospective studies on the potential utility of EGFR isoform ratios in predicting and/or monitoring disease recurrence, and in further stratifying patients for therapy.
Recent advances in breast cancer treatments include new uses of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone-receptor (ER) positive breast cancer, Herceptin for early stage HER-2 positive breast cancer, as well as potential uses of EGFR-targeted therapy in tamoxifen-resistant or ER-negative breast cancer. Unfortunately, we cannot yet accurately predict which patients will respond to a given treatment. Human epidermal growth factor receptor (EGFR/HER-1) is a potent oncogene, which frequently is overexpressed in breast tumors, where high levels of expression have been correlated with resistance to hormone therapy and poor patient prognosis. However, there is disagreement concerning the prognostic value of EGFR in breast cancer and consequently, it is not widely used in the clinic. We recently discovered that a naturally-occurring variant of the human EGFR, i.e., soluble EGFR (sEGFR), also is expressed in breast tumors. In addition, sEGFR has the potential to inhibit the action of full-length EGFR, and our recent studies suggest that sEGFR overexpression in tumors may be a favorable prognostic factor. We suspect that co-expression of these two EGFR variants in breast tumors has confounded earlier studies examining EGFR as a prognostic indicator. Therefore, the objective of this proposal is to determine which of these variants serves as a better predictor of disease recurrence, or if the measurement of both these proteins together will further improve their prognostic value. We hypothesize that the ratio of full-length EGFR to sEGFR expression levels in breast tumors will have prognostic value for patients. Specifically, we propose to (1) develop a test that can separately measure full-length EGFR and sEGFR protein expression in breast tumors; and (2), using this test, determine the prognostic utility of the combined expression of these EGFR variants in breast cancer tissues. To accomplish this objective, we will take advantage of a new automated technology, which can objectively quantify protein expression levels in tumor tissue, to analyze a large number of breast tumors, which already have been extensively characterized for many clinical parameters, including patient survival. The results of this study will help to clarify the relative importance of both full-length and soluble EGFR variant expression in breast cancer and may ultimately lead to better treatment selection strategies for breast cancer patients.