ErbB2 Receptor Immunoreactivity in Prostate Cancer: Relationship to the Androgen Receptor, Disease Severity at Diagnosis and Disease Outcome

Abstract

BackgroundErbB2 is a member of the epidermal growth factor family of tyrosine kinases that is centrally involved in the pathogenesis of prostate cancer and several studies have reported that a high expression of this protein has prognostic value. In the present study, we have investigated whether tumour ErbB2 immunoreactivity (ErbB2-IR) has clinically useful prognostic value, i.e. that it provides additional prognostic information to that provided by routine clinical tests (Gleason score, tumour stage).Methodology/Principal FindingsErbB2-IR was measured in a well-characterised tissue microarray of tumour and non-malignant samples obtained at diagnosis. Additionally, mRNA levels of ErbB2-IR in the prostate were determined in the rat following manipulation of circulating androgen levels. Tumour ErbB2-IR was significantly associated with the downstream signalling molecule phosphorylated-Akt and with the cell proliferation marker Ki-67. The significant association of tumour ErbB2-IR with the Gleason score at diagnosis was lost when controlled for the association of both parameters with Ki-67. In the rat prostate, mRNA for ErbB2 was inversely associated with circulating androgen levels. There was no association between ErbB2-IR and the androgen receptor (AR)-IR in the tumours, but an interaction between the two parameters was seen with respect to their association with the tumour stage. Tumour ErbB2-IR was confirmed to be a prognostic marker for disease-specific survival, but it did not provide significant additive information to the Gleason score or to Ki-67.Conclusions/SignificanceIt is concluded that tumour ErbB2-IR is of limited clinical value as a prognostic marker to aid treatment decisions, but could be of pathophysiological importance in prostate cancer.

PCA3 long noncoding RNA modulates the expression of key cancer-related genes in LNCaP prostate cancer cells

“…The differentially expressed genes reported here have known roles as modulators of cell survival, especially ERRB2 [23], PI3K [24], VEGF [25], and TERT [26]. Furthermore, some of these genes can regulate AR signaling, such as BRCA [27], ERBB2 [28], FOS [29], PI3K [30], BAD [31], TERT [32], and PLAUR [33]. A similar approach demonstrated a PCGEM1-associated gene expression signature that was significantly repressed in response to androgen ablation therapy and in hormone-refractory versus hormone-naive PCa patients [17].…”

Immunoreactivity for prostate specific antigen and Ki67 differentiates subgroups of prostate cancer related to outcome

“…The PSA low/Ki67 high group was enriched for cases with high Gleason score, advanced stage, early metastasis and, accordingly, poor prognosis, and probably identifies patients that irrespectively of Gleason score may need early active treatment. The association with increased pEGF-R [13], ErbB2 [28], and pAkt [29] signaling in the tumor epithelium, and with multiple signs of a particularly active tumor stroma response [18, 19], such as decreased stroma androgen receptors [30] and caveolin-1 [31], increased angiogenesis [15], high stroma hyaluronic acid [32] and a M2-macrophage (CD163+) [33] and mast cell- [34] associated inflammation suggest several potential targets that deserve future attention. This subgroup of tumors was apparently also associated with expression of the TRMPSS2-ERG fusion gene [35] and with changes in the so called tumor instructed normal tissue, see [8–11], although of moderate magnitude, separating it from prostates with less aggressive tumors.…”