Expression and Nuclear Localization of ErbB3 in Prostate Cancer

Abstract

Purpose: The ErbB1and ErbB2 receptors have been implicated in prostate cancer progression, but less is known about the role and biology of other ErbB receptor family members in prostate cancer. The aim of this study was to analyze the expression and localization of ErbB3 in prostate tissues and prostate cancer cell lines. Experimental Design: Immunohistochemistry of ErbB3 was done on prostate cancer tissue sections from 143 patients and on a tissue microarray containing 390 cores of radical prostatectomy-derived specimens representing normal, prostatic intraepithelial neoplasia, and malignant tissues from 81 patients. ErbB3 subcellular localization was studied by Western blot analysis in LNCaP, 22Rv1, PC-3, and DU145 prostate cancer cell lines. Results: Immunohistochemistry analysis of prostate cancer tissues revealed that >90 % of prostate cancer tissues displayed cytoplasmic ErbB3 staining. Minimal ErbB3 nuclear staining was observed in normal prostate tissues and benign prostatic hyperplasia tissues; in contrast, ErbB3 was frequently localized in the nucleus of cancerous tissues. This nuclear localization was more frequent (P < 0.001) in hormone-refractory tissues (17 of 17, 100%) compared with hormone-sensitive samples (37 of 92, 40.2%). Additionally, in the tissue microarray, increased nuclear ErbB3 was associated with increasing Gleason grade. Interestingly,Western blot analysis of cytoplasmic and nuclear subcellular fractions showed that ErbB3 nuclear localization was more prevalent in hormone-sensitive prostate cancer cell lines (LNCaP and 22Rv1) compared with hormone-insensitive cell lines (PC-3 and DU145). Conclusions: ErbB3 nuclear localization discriminates normal from malignant prostate tissues and between tumors from hormone-sensitive versus hormone-refractory prostate cancer. ErbB3 nuclear staining seems to be associated with risk of disease progression. The high frequency of ErbB3 nuclear localization in hormone-refractory tissues indicates that ErbB3 warrants further study to understand its association with prostate cancer disease progression.Prostate cancer is the second leading cause of cancer death among North American men. In 2003, prostate cancer was the most frequently diagnosed cancer in men, accounting for 30% of newly diagnosed cases and 10% of deaths (1). Improving the treatment of prostate cancer will require early diagnosis and appropriate therapeutic decisions based on a better understanding of the biology of prostate cancer and the underlying molecular events that predict disease progression.The ErbB receptor family consists of four receptors: ErbB1/ epidermal growth factor receptor (EGFR), ErbB2/Her2, ErbB3, and ErbB4 (2, 3). ErbB signaling produces a diversity of responses generated by three levels of molecular interactions. The first is ligand-receptor binding, the second is homodimerization and heterodimerization, and the third is associated with distinct sets of cytoplasmic signaling proteins largely dependent on the nature of the active dimer formed (4). Previous stu...

The ERBB3 receptor in cancer and cancer gene therapy

“…273 Finally, additional complexity is added by prostate cancer-related differences in the intracellular localization and in the processing and secretion of ERBB3. Prostate cancers, especially hormone refractory ones, show increased nuclear ERBB3, but in cancer cell lines nuclear ERBB3 was more notable in the hormone-sensitive ones, 79 and biochemical recurrence of prostate cancers was significantly associated with reduced nuclear localization. 274 A secreted isoform of ERBB3 was identified in 41/45 prostate cancer bone metastases and in activated osteoblasts and new bone matrices, but not in epithelial cells of primary cancers.…”

“…79 Its nuclear levels were low or absent in nonmalignant tissue and higher in hormone refractory compared with hormone-sensitive cancers and so were apparently correlated with tumor progression. In contrast, nuclear ERBB3 was higher in prostate cancer cell lines that were androgen responsive.…”

“…[248][249][250] Furthermore, ERBB2/ERBB3 complexes caused AKT-independent phosphorylation of the androgen receptor that stabilized the protein and enhanced its transcriptional activity. 248 Increased expression of ERBB3 in prostate cancers, compared with normal prostate, has been demonstrated by immunohistochemistry in several studies 79,[251][252][253][254] and was associated with poor prognosis. 252 Microarray analyses have likewise shown an increase in ERBB3 mRNA in these cancers.…”

The epidermal growth factor receptor family: Biology driving targeted therapeutics

“…Full-length EGFR, ErbB2, and ErbB3 as well as truncated constitutively active ErbB2 and truncated C-terminal ErbB4 (s80, E4ICD) have been found in the nucleus of cells [62][63][64][65][66][67][68][69][70]. EGFR has been proposed as a transcription factor as localization to the nucleus is associated with increased CyclinD1 expression [64].…”

Bone Microenvironment and Androgen Status Modulate Subcellular Localization of ErbB3 in Prostate Cancer Cells

“…Moreover, high ErbB-3 protein expression has been linked with poor prognosis in endometrioid carcinoma of the ovary (7) and with short survival in advanced non -small cell lung carcinoma (8). Several reports indicate that ErbB-3 expression increases in parallel with the malignancy of prostate cells, implicating ErbB-3 in the progression of prostate cancer (9)(10)(11)(12). However, information is limited on the expression of ErbB-3 in the metastasis of prostate cancer.…”