Nuclear expression of epidermal growth factor receptor is a novel prognostic value in patients with ovarian cancer

Abstract

The epidermal growth factor receptor (EGFR) has previously been detected in the nucleus of cancer cells and primary tumors. We have reported that EGFR translocates from the plasma membrane to the nucleus. Accumulation of nuclear EGFR is linked to increased DNA synthesis and proliferation; however, the pathological significance of nuclear EGFR is not completely understood. Here, we sought to determine the predictive value of EGFR for the survival of ovarian cancer patients, through the examination of 221 cases of ovarian cancer tissues by immunohistochemical analysis to determine nuclear EGFR expression. In addition, we also examined cyclin D1 and Ki-67 through immunohistochemisty. Furthermore, we examined nuclear EGFR levels in ovarian cancer cell lines treated with EGF, and primary ovarian tumor tissue using immunofluorescence analysis. Nuclear fractions extracted from serum-starved cells treated with or without EGF were subjected to SDS–PAGE and Western blot analyses. We found that 28.3% of the cohort had high levels of nuclear EGFR, while 22.5% had low levels of nuclear EGFR, and 49.2% were negative for nuclear EGFR. Importantly, there was an inverse correlation between high nuclear EGFR, cyclin D1, and Ki-67 with overall survival (P < 0.01, P < 0.09, P < 0.041). Additionally, nuclear EGFR correlated positively with increased levels of cyclin D1 and Ki-67, both indicators for cell proliferation. Our findings indicate a pathological significance of nuclear EGFR that might be important for predicting clinical prognosis of ovarian cancer patients.

RNA helicase A is a DNA-binding partner for EGFR-mediated transcriptional activation in the nucleus

“…S2A). To confirm further the nuclear location of EGFR/RHA complexes, sequential photosections of a nucleus were examined, and EGFR/RHA complexes were clearly detected in middle sections (i.e., planes [11][12][13][14] in both MDA-MB-468 and HeLa cells (Fig. S2 B and C).…”

“…Nuclear EGFR has been demonstrated to contribute to cancer cell resistance to cetuximab and radiation treatment (5,6) and to be negatively correlated with overall survival of patients with multiple cancer types (7)(8)(9)(10)(11). Moreover, nuclear EGFR interacts with signal transducer and activator of transcription 3 (STAT3), signal transducer and activator of transcription 5A (STAT5A), E2F1, DNA-dependent protein kinase (DNA-PK), and proliferating cell nuclear antigen (PCNA) and plays important roles in cell transformation, proliferation, and DNA repair and replication (12)(13)(14)(15)(16).…”

Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

“…[21][22][23][24][25] Increased nuclear EGFR localization correlates with poor clinical outcome in patients with breast cancer, 26 oropharyngeal SCC 27 and ovarian cancer. 28 Recent reports have characterized a novel nuclear localization sequence in EGFR and its family members. [29][30][31] Furthermore, transport mechanisms for EGFR to the nucleus have been described previously.…”

PML represses lung cancer metastasis by suppressing the nuclear EGFR-mediated transcriptional activation ofMMP2

“…21,24 Clinical studies have indicated that increased nEGFR expression is associated with poor prognosis. 25,26 The nuclear translocation of EGFR is initiated by ligandinduced endocytosis. 27 Endosome-associated EGFR is recognized by importin b in the cytoplasm and is then transported to the inner nuclear membrane (INM) via the INTERNET (integral trafficking from the ER to the nuclear envelope transport) mechanism.…”