Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth

Gregory, Christopher; Whang, Young E.; McCall, Wesley; Fei, Xiaoyin; Liu, Yuanbo; Ponguta, Liliana Angélica; French, Frank S.; Wilson, Elizabeth M.; Earp, H. Shelton

doi:10.1158/1078-0432.ccr-04-1158

Cited by 123 publications

(122 citation statements)

References 49 publications

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“…2). (41) HER2 and HER3, in response to heregulin binding, increases ligand-dependent AR transactivation of reporter genes. (41) The relevance of these to prostate cancer in vivo remains to be clarified.…”

Section: Tmprss2mentioning

confidence: 98%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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SummaryProstate cancer is the most frequently diagnosed nonskin cancer and the third leading cause of cancer mortality in men. In the initial stages, prostate cancer is dependent on androgens for growth, which is the basis for androgen ablation therapy. However, in most cases, prostate cancer progresses to a hormone refractory phenotype for which there is no effective therapy available at present. The androgen receptor (AR) is required for prostate cancer growth in all stages, including the relapsed, ''androgen-independent'' tumors in the presence of very low levels of androgens. This review focuses on AR function and AR-target genes and summarizes the major signaling pathways implicated in prostate cancer progression, their crosstalk with each other and with AR signaling. This complex network of interactions is providing a deeper insight into prostate carcinogenesis and may form the basis for novel diagnostic and therapeutic strategies. IntroductionProstate adenocarcinoma is the most frequently diagnosed non-cutaneous male malignancy and the third leading cause of cancer-related death in men in most western industrialized countries. (1) It is estimated that around 660,000 men worldwide will be diagnosed with prostate cancer and 250,000 men will die from it in 2010; thus, it will remain a major health problem in the future. (1) It was more than 60 years ago that the important role of male sex hormones (androgens) for the development and growth of prostate cancer was demonstrated. (2) Accordingly, androgen ablation therapy has been the main line of therapy for prostate cancer. Therefore, much of the focus in prostate cancer research to date has naturally been on androgens, how to decrease the androgens in the circulation and how to inhibit the androgen receptor (AR).In addition to AR signaling, it has now become evident that other signaling pathways, as well as non-genomic and genomic alterations, are involved in prostate cancer development and progression. Furthermore, recent studies indicated that signaling through AR has a critical role even after androgen ablation and disease progression (for review see Ref.3). In the following sections, we give an overview of androgen signaling in prostate cancer, with a special focus on recent findings about AR function and AR target genes. We then review the involvement of other central signaling pathways in prostate cancer, with a special focus on their cross-talk with the AR signaling pathway. Clinical implications of these findings and potential directions for future research are also outlined.

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Section: Tmprss2mentioning

confidence: 98%

Androgen signaling and its interactions with other signaling pathways in prostate cancer

2007

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“…212 In the CWR-R1 recurrent prostate cancer cell line, there was evidence for an autocrine pathway involving NRG and low-level constitutive ERBB2/ERBB3 activation leading to androgen receptor transactivation. 266 Xenografts of three androgen-dependent cell lines (CWR22, LNCaP and LNCaP35) also showed growth inhibition under treatment with 2C4 monoclonal antibody, although effects of NRG on these cells in culture were not reported. 212 One of the consequences of NRG activation of ERBB3 is release of the EBP1 protein.…”

Section: Prostate Cancermentioning

confidence: 99%

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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“…These signalling pathways may activate the AR without ligand, culminating in androgenreceptor signalling, leading to cellular proliferation, migration, and survival. The references for the reactions cited in Figure 1 are as follows: Reaction 1, Heinlein and Chang, 2004; Reaction 2, Heinlein and Chang, 2004;Reaction 3, Heinlein and Chang, 2004;Reaction 4, Heinlein and Chang, 2004;Reaction 5, Heinlein and Chang, 2004;Reaction 6, Heinlein and Chang, 2004;Reaction 7, Brass et al, 1995;Ravenna et al, 1995;Itoh et al, 1998;Schwartz et al, 1998;Heinlein and Chang, 2004;Hammarsten et al, 2007;Pignon et al, 2009;Reaction 8, Nishi et al, 1996;Reaction 9, Traish and Wotiz, 1987;St-Arnaud et al, 1988;Reaction 10, Sugita et al, 2004;Gregory et al, 2005;Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 11, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 12, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 13, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009;Reaction 14, Migliaccio et al, 2006;Léotoing et al, 2007;Zhu and Kyprianou, 2008;Recchia et al, 2009. Abbreviations: AKT, protein kinase B; AR, androgen receptor; ARE, androgen response element; 5a-DHT, d...…”

Section: Loss Of Regulation Of Egfr Expression In Pca By Androgens Stmentioning

confidence: 99%

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

2009

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Androgen deprivation therapy reduces prostate cancer (PCa) tumour growth; however, disease relapse often ensues independently of androgen stimulation, producing androgen-refractory tumours with increased invasion, proliferation, and malignancy. Androgens downregulate epidermal growth factor receptor (EGFR) in normal prostate but not in PCa. Thus, loss of EGFR regulation and altered signalling may, in part, explain the transition of prostate tumours from androgen dependent to androgen independent. Studies in animal models, PCa cell lines, and tumour specimens suggest that androgens modulate prostate growth and function through mechanisms that involve 'cross-talk' between androgen receptor (AR) and growth factor receptor signalling pathways. The objective of this review is to discuss the paradoxical relationship between androgen regulation of EGFR in normal prostate and PCa. We reviewed the literature from mid-1980s through 2009 to assess the relationship between androgens and EGFR function in modulating the growth of normal prostate and PCa. Loss of androgen regulation of EGFR in PCa may be responsible for increased tumour growth, invasion, and metastasis, with important implications on the clinical management of PCa. We advance the hypothesis that a molecular switch, responsible for downregulating EGFR expression by androgens in the normal prostate, is either lost or modified in PCa.

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Heregulin-Induced Activation of HER2 and HER3 Increases Androgen Receptor Transactivation and CWR-R1 Human Recurrent Prostate Cancer Cell Growth

Cited by 123 publications

References 49 publications

Androgen signaling and its interactions with other signaling pathways in prostate cancer

Androgen signaling and its interactions with other signaling pathways in prostate cancer

The ERBB3 receptor in cancer and cancer gene therapy

Epidermal growth factor receptor expression escapes androgen regulation in prostate cancer: a potential molecular switch for tumour growth

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