Epithelial Cell Adhesion Molecule (EpCAM) Is Overexpressed in Breast Cancer Metastases Compared to Matched Primary Cancers
A Cimino, M Halushka, P Illei, D Molavi, X Wu, S Sukumar, P Argani. The Johns Hopkins Hospital, Baltimore, MD
Background: The transmembrane protein EpCAM has diverse roles in cell adhesion, proliferation, and migration and is overexpressed in breast carcinoma relative to normal breast epithelium. While preclinical data suggest a role for EpCAM in metastases, a study of breast cancer micrometastases to bone marrow (Clin Cancer Res 2003; 9:2598-2604) suggested that EpCAM expression is decreased after first-line chemotherapy. No prior studies have compared EpCAM expression in metastatic breast carcinoma (MBC) versus matched primary breast carcinoma (PBC).
Design: Fifteen rapid autopsies (post mortem intervals <4 hours) were performed on patients who died of MBC. Single patient tissue microarrays (TMAs) were constructed from paraffin tissue blocks of patients' archived PBC and from multiple MBCs sampled at autopsy. Fifteen TMA slides containing 145 spots of PBCs and 778 spots derived from 180 different MBCs were labeled by immunohistochemistry for EpCAM. EpCAM expression was scored as labeling intensity (1-3) multiplied by percent membrane labeling (0-100%). Each patient's average PBC and MBC labeling score was subclassified as low (score 20-100), moderate (score 101-200), or high (score 201-300). Quantitative reverse transcription-polymerase chain reaction (QRT-PCR) was performed on microdissected unmatched PBCs and MBCs to quantify EpCAM mRNA expression.
Results: All PBCs and MBCs demonstrated membranous EpCAM labeling. PBCs exhibited low to moderate average EpCAM labeling. EpCAM labeling was statistically significantly increased in MBCs compared to matched PBCs in 12 of 15 patients (80%; p values ranging from <0.05 to <0.0001, t test), and strikingly so in 4 patients as illustrated below.
In the remaining 3 patients, EpCAM labeling was nonsignificantly increased in 1 and unchanged in 2. In all cases, EpCAM expression was uniform in all MBCs. Surprisingly, QRT-PCR did not show upregulation of EpCAM mRNA transcripts.
Conclusions: EpCAM is consistently upregulated in MBCs as compared to matched PBCs. The absence of increased RNA expression suggests a post-translational mechanism for protein overexpression. EpCAM is a promising therapeutic target for MBC.
Monday, March 9, 2009 9:30 AM
Poster Session I Stowell-Orbison/Autopsy Award # 22, Monday Morning