Her-2-neu Expression and Progression Toward Androgen Independence in Human Prostate Cancer

Signoretti, Sabina; Montironi, Rodolfo; Manola, Judith; Altimari, Annalisa; Tam, Carmen; Bubley, Glenn J.; Balk, Steven P.; Thomas, George V.; Kaplan, Irving; Hlatky, Lynn; Hahnfeldt, Philip; Kantoff, Philip W.; Loda, Massimo

doi:10.1093/jnci/92.23.1918

Cited by 333 publications

(264 citation statements)

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“…Furthermore, in prostate cancer cell lines, we found that androgen-sensitive LNCaP cells and castration-resistant C4-2 cells also overexpressed this protein (Figure 3). Our findings are consistent with the majority of patient-related reports in literature, [5][6][7][8]10,11 as well as some in vitro and animal model studies. 13,48,49 Furthermore, it has been recently reported that in men with long-term follow-up after HER-2 targeting of prostate cancer K-x Zhang et al radical prostatectomy, HER-2 expression when combined with percentage DNA index can be used clinically for prediction of progression, metastasis and prostate cancerspecific death.…”

Section: Discussionsupporting

confidence: 93%

“…In prostate cancers, overexpression of HER-2 has been reported to be associated with progression to androgen independence, [5][6][7][8]10,11 although some contradictory results have also been reported. 39,40 To normalize variables such as fixation and staining procedures, which could account for the reported differences, we used a TMA approach where 105 unique prostate tissue cores from 35 patients were immunostained for HER-2 simultaneously.…”

Section: Resultsmentioning

confidence: 99%

“…[5][6][7][8][9][10][11] Overexpression of HER-2, which causes activation of the PI3k/AKT pathways and promotion of cell proliferation, has been proposed to be a survival factor for prostate cancer cells in the absence of androgens. 10,12 Moreover, this can lead to the activation of the androgen receptor and enhancement of binding of this nuclear receptor to the promoters of androgenregulated genes. 13 Overall, overexpression of HER-2 in prostate cancer samples has been associated with lower survival.…”

Section: Introductionmentioning

confidence: 99%

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Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Moussavi

et al. 2009

Cancer Gene Ther

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In this study, we took advantage of the overexpression of human epidermal growth factor receptor 2 (HER-2) in prostate cancers to design lentiviruses with modified envelope proteins that bind antibodies to specific cell-surface antigens. When bound to trastuzumab (Herceptin, Genentech, CA), lentiviruses were able to selectively infect androgen-sensitive LNCaP and castrationresistant C4-2 human prostate cancer cell lines, both of which express high levels of HER-2. To test for a therapeutic effect, we engineered our antibody-binding lentiviruses to express thymidine kinase, which can convert the non-toxic pro-drug ganciclovir (GCV) into a cytotoxic form. LNCaP and C4-2 cells infected by these viruses were sensitive to GCV killing. In vivo, C4-2 xenograft tumors treated either intratumorally or i.v. with trastuzumab-bound lentivirus expressed luciferase, although the latter route was less tumor specific. When a prostate-specific promoter for governing luciferase expression was combined with trastuzumab-mediated delivery, there was a further enrichment in targeting viral gene expression in prostate tumors. In conclusion, we found that although prostate cancers that express high levels of HER-2 are resistant to the killing effects of trastuzumab, they can be targeted for selective gene expression and destruction by viruses with envelope proteins engineered to bind this antibody.

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Section: Discussionsupporting

confidence: 93%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Moussavi

et al. 2009

Cancer Gene Ther

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“…Additionally, EGF or heregulin had no effect on promoting the adhesive ability of C-33 cells (Supplementary Figure 4). We propose that in androgenindependent, AR-positive PCa cells, ErbB-2 protein is constitutively activated and/or elevated as seen in clinical samples due, in part, to the loss or null of cPAcP expression (Signoretti et al, 2000;Veeramani et al, 2005). In those advanced PCa cells, signal pathways initiated by highly activated ErbB-2 lead to a sustained activation of PYK2 and PYK2-mediated functions, which differs from the transient effect activated by ErbB ligands (Zrihan-Licht et al, 2000;van der Horst et al, 2005;Park et al, 2006).…”

Section: Discussionmentioning

confidence: 97%

“…In most prostate epithelia, only three members of this family, but not ErbB-4, are expressed (Robinson et al, 1996). In prostate carcinomas, the erbB-2 gene is not amplified and its protein level is elevated in some advanced tumors during androgen ablation therapy (Signoretti et al, 2000). In androgen-independent human PCa cells, ErbB-2 is greatly activated by tyrosyl phosphorylation, at least in part due to the low or null expression of cellular prostatic acid phosphatase (cPAcP), a prostate-unique tyrosine phosphatase that dephosphorylates ErbB-2 .…”

Section: Introductionmentioning

confidence: 99%

ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells

et al. 2007

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Aberrant regulation in the adhesive ability of cancer cells is closely associated with their metastatic activity. In this study, we examine the role of ErbB-2 in regulating the adhesive ability of androgen receptor (AR)-positive human prostate cancer (PCa) cells, the major cell population of PCa. Utilizing different LNCaP and MDA PCa2b cells as model systems, we found that ErbB-2 activity was correlated with PYK2 activity and adhesive ability in those cells. Increased ErbB-2 expression or activity in LNCaP C-33 cells enhanced PYK2 activation and cell adhesion, while the high PYK2 activity and the rapid adhesion of LNCaP C-81 cells were decreased by diminishing ErbB-2 expression or activity. Knockdown studies revealed the predominant role of ErbB-2 in regulating LNCaP C-81 cell adhesion. Coimmunoprecipitation showed that C-81 cells had increased interaction between ErbB-2 and PYK2. Elevated ErbB-2 activity in LNCaP cells correlated with increased ERK/MAPK activity and enhanced adhesive ability, which were abolished by the expression of K457A-PYK2 mutant or the treatment of PD98059, a MEK inhibitor. In summary, our data suggested that ErbB-2, via PYK2-ERK/MAPK, upregulates the adhesive ability of AR-positive human PCa cells.

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The Molecular Biology of Prostate Cancer

Waxman¹

2002

Treatment Options in Urological Cancer

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Prostate cancer is the most frequently diagnosed malignancy among men in industrialized countries. In the United States, one in eight men will develop prostate cancer during their lifetime [1], and in 1999 approximately 37,000 died from the disease [2]. In England and Wales, 17,000 cases are diagnosed and there are nearly 9000 deaths annually from prostate cancer [3].Advances in our understanding of the molecular basis of cancer have led to the characterization of critical pathways regulating tumor growth, which should provide the potential for the development of more effective and less toxic targeted therapies. In 1941 Huggins and Hodges first demonstrated that malignant tumors arising from the prostate were responsive to androgen withdrawal. Since then, hormonal therapy has been established as the principal treatment modality for advanced disease.Over time,however,resistance to treatment occurs. As a result, there has been much interest not only in the molecular changes associated with prostate cancer but also in the molecular mechanisms of tumor resistance. This chapter describes the current status of research into the molecular biology of prostate cancer, with emphasis on recent progress.

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Her-2-neu Expression and Progression Toward Androgen Independence in Human Prostate Cancer

Abstract: Her-2-neu expression appears to increase with progression to androgen independence. Thus, therapeutic targeting of this tyrosine kinase in prostate cancer may be warranted.

Cited by 333 publications

References 46 publications

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

Lentiviruses with trastuzumab bound to their envelopes can target and kill prostate cancer cells

ErbB-2 via PYK2 upregulates the adhesive ability of androgen receptor-positive human prostate cancer cells

The Molecular Biology of Prostate Cancer

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