ErbB‐4 may control behavior of prostate cancer cells and serve as a target for molecular therapy

Ben‐Yosef, Rami; Starr, Alexander; Karaush, Victoria; Loew, Vered; Lev-Ari, Shahar; Barnea, Itay; Lidawi, Ghalib; Shtabsky, Alexander; Greif, Yoel; Yarden, Yosef; Vexler, Akiva

doi:10.1002/pros.20555

Cited by 16 publications

(15 citation statements)

References 40 publications

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“…A few studies have analyzed the role of HER4 receptor in PCa, and the conclusions are controversial. Some investigators have correlated the expression of HER4 with enhanced prostate cell proliferation and migratory capacity (64,65), but others have reported that HER4 has a tumor-suppressive effect (66,67). HER4 activity has also been related to acquired resistance to anti-EGFR therapies, as the signaling through the PI3K/Akt survival pathway can be alternatively activated by HER4 (39).…”

Section: Discussionmentioning

confidence: 99%

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Carrión-Salip

Panosa

Menendez

et al. 2012

International Journal of Oncology

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Abstract. The deregulation of the epidermal growth factor receptor (EGFR) pathway plays a major role in the pathogenesis of prostate cancer (PCa). However, therapies targeting EGFR have demonstrated limited effectiveness in PCa. A potential mechanism to overcome EGFR blockade in cancer cells is the autocrine activation of alternative receptors of the human EGFR (HER) family through the overexpression of the HER receptors and ligands. In the present study, we were interested in analyzing if this intrinsic resistance mechanism might contribute to the inefficacy of EGFR inhibitors in PCa. To this end, we selected two androgen-independent human prostate carcinoma cell lines (DU145 and PC3) and established DU145 erlotinib-resistant cells (DUErR). Cells were treated with three EGFR inhibitors (cetuximab, gefinitib and erlotinib) and the sensitivity to each treatment was assessed. The gene expression of the four EGFR/HER receptors and seven ligands of the HER family was analyzed by real-time PCR prior to and after each treatment. The receptors expression and activation were further characterized by flow cytometry and western blot analysis. EGFR inhibition rapidly induced enhanced gene expression of the EGF, betacellulin and neuregulin-1 ligands along with HER2, HER3 and HER4 receptors in the DU145 cells. In contrast, slight changes were observed in the PC3 cells, which are defective in the phosphatase and tensin homolog (PTEN) tumor suppressor gene. In the erlotinib-resistant DUErR cells, the expression of HER2 and HER3 was increased at mRNA and protein levels together with neuregulin-1, leading to enhanced HER3 phosphorylation and the activation of the downstream PI3K/Akt survival pathway. HER3 blockage by a monoclonal antibody restored the cytostatic activity of erlotinib in DUErR cells. Our results confirm that the overexpression and autocrine activation of HER3 play a key role in mediating the resistance to EGFR inhibitors in androgen-independent PCa cells.

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Section: Discussionmentioning

confidence: 99%

Androgen-independent prostate cancer cells circumvent EGFR inhibition by overexpression of alternative HER receptors and ligands

Carrión-Salip

Panosa

Menendez

et al. 2012

International Journal of Oncology

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“…Based on our earlier findings, 17 we selected two clones of Cl-1 cells: clone #3 and clone #7. The highly proliferative clone #3 had high ErbB4 expression and the low proliferative clone #7 had low ErbB4 expression (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Our previous studies 17,18 revealed that overexpression of ErbB4 is present in 38% of prostate cancer patients and that targeting ErbB4 receptor in in vivo and in vitro using an androgen-resistant cell line is an effective treatment approach.…”

Section: Introductionmentioning

confidence: 99%

“…[14][15][16] We had earlier evaluated the expression of ErbB4 in PC3, Cl-1 and Du145 cell lines and found that they had high levels of ErbB4 expression: those cells proliferated faster than cells with low levels of ErbB4 expression and their survival was decreased by the use of an antiErbB4 monoclonal antibody (mAb). 17 Radiation therapy alone or in combination with hormonal therapy is commonly used in prostate cancer. While being effective in the treatment of patients with low and intermediate risk, this combined approach is only partially effective in high-risk patients.…”

Section: Introductionmentioning

confidence: 99%

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Anti-ErbB4 targeting approaches for prostate cancer treatment

Vexler

Lidawi²,

Loew³

et al. 2008

Cancer Biology & Therapy

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Methods: Clones with low and high expression of ErbB4 isolated by a limited dilution technique from an androgen-independent Cl-1 cell line were used. The cells from these clones were exposed to XRT (single dose of 2-6 Gy) and to anti-ErbB4 monoclonal antibody (mAb). The XTT test was used to measure cell survival. In addition, tumor-bearing nude mice were treated either by XRT, mAb or by a combined treatment. Tumor sizes were recorded at given time points.Conclusion: Anti ErbB4 combined with XRT is possibly more effective than each modality alone in prostate cancer.

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“…12 The ability of ERBB4 antibodies to slow the growth of several prostate cancer cell lines in vitro and in mouse xenograft models suggests that this gene may possess biological activity in prostate tissue. 13 Therefore, in contrast to other epithelial tumors, the prostate may be a site in which ERBB4 function could be targeted as an anti-cancer therapy. The role of ERBB4 in promoting cell growth, however, remains controversial as high protein expression correlates to an extended time to relapse in hormone-sensitive prostate tumors 12 and ERBB4 overexpression induces prostate cancer cells to growth arrest.…”

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confidence: 99%