Concomitant ERBB2-ERBB3 Expression in Prostatic Large Duct Carcinoma.
Marcela A Salomao, Luiz Araujo, Mahesh Mansukhani, Matthias J Szabolcs. Columbia University Medical Center, New York, NY
Background: The ERBB2-ERBB3 receptor tyrosin kinase (RTK) heterodimer has been linked to aggressive prostate cancer due to androgen independent activation of multiple signaling pathways involved in oncogenesis and tumor progression. Prostatic large duct carcinoma of the periurethral ducts (PLDC), comprising up to 5% of all prostate cancers, behaves more aggressively than its acinar counterpart (PAC). This study was undertaken to determine whether PLDCs display higher levels of ERBB RTK expression compared to PACs, similar to what is seen in the non-neoplastic prostate.
Design: Prostate tissue from TURP specimens (n=10) was used to determine the distribution of ERBBs in the normal prostate. A total of 220 cases of prostate cancer with known patient age, stage and Gleason's score were selected from the files in the Surgical Pathology Division of CUMC. Tissue microarrays were built and immunostained for ERBB1 (EGFR), ERBB2 (NEU) and ERBB3 and scored as no, weak or strong staining (>15% cells). All PLDCs (n=34) and a control set of age and stage-matched PACs cases were stained for C-MYC to determine overall signaling pathway activation. The proliferation index was determined by Ki-67 labeling. Fisher exact test and student's T-test was used in the data analysis.
Results: ERBB1 and 3 were present in the basal cells of benign prostatic acini, with NEU absent. Both NEU and ERBB3 but not EGFR consistently displayed strong labeling of benign prostatic urethra and periurethral prostatic ducts. PLDCs (n=34) vs. PACs (n=186) showed strong staining for EGFR in 35.3% vs. 22.6% (p=0.13), for NEU in 41.2% vs. 10.8% (p<10-5) and for ERBB3 in 94.1% vs. 62.4% (p<10-4). To overcome its defective kinase activity, ERBB3 needs to dimerize with another ERBB family member. Co-expression of ERBB3 with either EGFR or NEU occurred in 58.8% (20/34) of PLDCs, but only 19.4% (36/186) of PACs (p<10-6). ERBB3-positive PLDCs display high levels of NEU (70%), whereas ERBB3-positive PACs upregulate EGFR (69.4%). PLDCs have a 4x higher Ki-67 index (p<10-4, T-test) and strong MYC signaling (58.8% vs. 20.6%, p<0.0001).
Conclusions: In this study, we show that prostatic PLDC recapitulates the phenotype of prostatic periurethral ducts with high prevalence of concomitant NEU and ERBB3 expression. The high levels of NEU and ERBB3 in PLDC could explain the higher proliferation indices and MYC levels when compared to PAC due to known potent androgen independent activation of tumor signaling pathways of the ERBB2/ERBB3 dimer. This distinct molecular phenotype may explain the more aggressive clinical behavior of ductal prostatic carcinoma.
Category: Genitourinary (including renal tumors)
Monday, February 28, 2011 1:00 PM
Poster Session II # 155, Monday Afternoon