A potential autocrine loop between heregulin‐alpha and erbB‐3 receptor in human prostatic adenocarcinoma

Leung, Hing Y.; Weston, J.; Gullick, William J.; Williams, Gwyn Samuel

doi:10.1046/j.1464-410x.1997.30412.x

Cited by 53 publications

(46 citation statements)

References 5 publications

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“…This report also indicates that biological responses to heregulin both in vitro and in vivo are directly correlated with HER-2/neu expression levels. This con®rms results from other investigators indicating that heregulin signaling through HER-3 and HER-4 may be dependent on HER-2/neu expression levels in breast (Riese et al, 1995;Beerli et al, 1995) as well as prostate cells (Leung et al, 1997;Grasso et al, 1997). The observed variability for the expression of the di erent RTK type I, in particular the changes in HER-3 number post HER-2 transfection, most likely have an impact on the extent of the e ect of HRG.…”

Section: Discussionsupporting

confidence: 88%

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Akita²,

et al. 1999

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The heregulins are a family of ligands with ability to induce phosphorylation of the p185 HER-2/neu receptor. Various investigators have reported a variety of responses of mouse and human breast and ovarian cells to this family of ligands including growth stimulation, growth inhibition, apoptosis and induction of di erentiation in cells expressing the HER-2/neu receptor. Some of the disparity in the literature has been attributed to variations in the cell lines studied, ligand dose applied, methodologies utilized or model system evaluated (i.e. in vitro or in vivo). To evaluate the e ects of heregulin on normal and malignant human breast and ovarian epithelial cells expressing known levels of the HER-2/ neu receptor, this report presents the use of several di erent assays, performed both in vitro and in vivo, in vitro proliferation assays, direct cell counts, clonogenicity under anchorage-dependent and anchorage-independent conditions, as well as the in vivo e ects of heregulin on human cells growing in nude mice to address heregulin activity. Using a total of ®ve di erent biologic assays in nine di erent cell lines, across two di erent epithelia and over a one log heregulin dose range, we obtained results that clearly indicate a growth-stimulatory role for this ligand in human breast and ovarian epithelial cells. We ®nd no evidence that heregulin has any growth-inhibitory e ects in human epithelial cells. We also quantitated the amount of each member of the type I receptor tyrosine kinase family (RTK I, i.e. HER-1, HER-2, HER-3 and HER-4) in the cell lines employed and correlated this to their respective heregulin responses. These data demonstrate that HER-2/neu overexpression itself a ects the expression of other RTK I members and that cells expressing the highest levels of HER-2/neu have the greatest response to HRG.

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Section: Discussionsupporting

confidence: 88%

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Akita²,

et al. 1999

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“…[260][261][262][263][264] Findings regarding NRG expression have been mixed. While NRG1 was expressed in the majority of prostate cancers as observed by immunohistochemistry, 252 other studies have found this ligand to be absent from prostate cancers 253 and malignant cell lines, 253,258 although expression of NRG in prostate stroma 253 and other cell types could have effects on cancers within the organ.…”

Section: Prostate Cancermentioning

confidence: 86%

“…[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.…”

Section: Prostate Cancermentioning

confidence: 99%

“…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. [254][255][256] ERBB3 was one of 15 genes whose expression levels had promise as diagnostic and prognostic markers for prostate cancer; EGFR and ERBB2 were also in this cluster.…”

Section: Prostate Cancermentioning

confidence: 99%

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The ERBB3 receptor in cancer and cancer gene therapy

2008

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ERBB3, a member of the epidermal growth factor receptor (EGFR) family, is unique in that its tyrosine kinase domain is functionally defective. It is activated by neuregulins, by other ERBB and nonERBB receptors as well as by other kinases, and by novel mechanisms. Downstream it interacts prominently with the phosphoinositol 3-kinase/AKT survival/mitogenic pathway, but also with GRB, SHC, SRC, ABL, rasGAP, SYK and the transcription regulator EBP1. There are likely important but poorly understood roles for nuclear localization and for secreted isoforms. Studies of ERBB3 expression in primary cancers and of its mechanistic contributions in cultured cells have implicated it, with varying degrees of certainty, with causation or sustenance of cancers of the breast, ovary, prostate, certain brain cells, retina, melanocytes, colon, pancreas, stomach, oral cavity and lung. Recent results link high ERBB3 activity with escape from therapy targeting other ERBBs in lung and breast cancers. Thus a wide and centrally important role for ERBB3 in cancer is becoming increasingly apparent. Several approaches for targeting ERBB3 in cancers have been tested or proposed. Small inhibitory RNA (siRNA) to ERBB3 or AKT is showing promise as a therapeutic approach to treatment of lung adenocarcinoma.

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“…However, studies of the role of ErbB2 in clinical prostate cancer remain inconclusive (Grossmann et al, 2001), and initial clinical trials indicate that the anti-ErbB2 antibody Herceptin (trastuzumab) does not show significant clinical activity as a single agent (Ziada et al, 2004). ErbB3 has not been as extensively studied, but analysis of clinical prostate cancer specimens indicates that overexpression of ErbB3 has been linked to a less favourable prognosis (Leung et al, 1997).…”

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confidence: 99%

Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling

Zhang

Hamburger

2004

Br J Cancer

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Although ErbB receptors have been implicated in the progression of prostate cancer, little is known about proteins that may mediate their interactions with the androgen receptor (AR). Ebp1, a protein cloned via its association with the ErbB3 receptor, binds the AR and inhibits androgen-regulated transactivation of wild-type AR in COS cells. As the complement of coregulators in different cells are important for AR activity, we determined the effect of Ebp1 on AR function in prostate cancer cell lines. In addition, we examined the regulation of Ebp1 function by the ErbB3/4 ligand heregulin (HRG). In this study, we demonstrate, using several natural AR-regulated promoters, that Ebp1 repressed transcriptional activation of wild-type AR in prostate cancer cell lines. Downregulation of Ebp1 expression in LNCaP cells using siRNA resulted in activation of AR in the absence of androgen. Ebp1 associated with ErbB3 in LNCaP cells in the absence of HRG, but HRG induced the dissociation of Ebp1 from ErbB3. In contrast, HRG treatment enhanced both the association of Ebp1 with AR and also the ability of Ebp1 to repress AR transactivation. These studies suggest that Ebp1 is an AR corepressor whose biological activity can be regulated by the ErbB3 ligand, HRG.

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A potential autocrine loop between heregulin‐alpha and erbB‐3 receptor in human prostatic adenocarcinoma

Cited by 53 publications

References 5 publications

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

Biologic effects of heregulin/neu differentiation factor on normal and malignant human breast and ovarian epithelial cells

The ERBB3 receptor in cancer and cancer gene therapy

Specificity and heregulin regulation of Ebp1 (ErbB3 binding protein 1) mediated repression of androgen receptor signalling

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