Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer

Gregory, Christopher; Fei, Xiaoyin; Ponguta, Liliana Angélica; He, Bin; Bill, Heather M.; French, Frank S.; Wilson, Elizabeth M.

doi:10.1074/jbc.m307649200

Cited by 195 publications

(184 citation statements)

References 91 publications

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“…Not the less, EGFR phosphorylation resulting from short-term incubation with bone stromal conditioned medium (containing 6% FBS) and suppression of in vivo bone metastasis formation following targeted inhibition of EGFR-dependent signalling have been demonstrated in androgen-independent prostate carcinoma PC3 cells [34]. Separately, EGFR and ERBB2 may facilitate androgen receptor-driven activity in prostate cancer at the level of target gene transcription in the absence or at low concentrations of androgens [35,36]. Yet, androgen receptor pathway genes, identified by systemlevel analysis of gene expression in primary tumor specimens from therapy-naïve prostate cancer patients, were reported to be down-regulated, with a few exceptions, in lymph-node metastases from the patients [37].…”

Section: Discussionmentioning

confidence: 99%

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

Bratland

Boender

Høifødt

et al. 2009

Clin Exp Metastasis

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Bone metastases in prostate cancer are predominantly osteoblastic. To study regulatory mechanisms underlying the establishment of prostate cancer within an osteoblastic microenvironment, human androgen-sensitive prostate carcinoma cells (LNCaP) were treated with culture medium conditioned by human osteoblast-derived sarcoma cells (OHS), and activated signalling pathways in the carcinoma cells were analyzed using microarrays with tyrosine kinase substrates. Network interaction analysis of substrates with significantly increased phosphorylation levels revealed that signalling pathways mediated by EGFR and ERBB2 were activated in LNCaP cells under OHS influence but also by androgen treatment. Activation of EGFR/ERBB2 signalling was also found in LNCaP cells in cocultures with OHS cells or osteoblastic cells that had been differentiated from human mesenchymal stem cells. Our experimental data suggests osteoblast-directed induction of signalling activity via EGFR and ERBB2 in prostate carcinoma cells and may provide a rationale for the use of EGFR or ERBB2 inhibition in systemic prevention or treatment of metastatic prostate cancer in the androgensensitive stage of the disease.

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Section: Discussionmentioning

confidence: 99%

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

Bratland

Boender

Høifødt

et al. 2009

Clin Exp Metastasis

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“…20 It has also been reported that the EGFR family modulates AR signaling and contributes androgenindependent tumor progression. [24][25][26][27][28] Expression levels of EGFR family were therefore evaluated as possible targets for NEU3 ( Figure 4d). NEU3 was found to increase EGFR and ERBB2 in mRNA and protein levels together with AR and PSA elevation in LNCaP cells under androgendeficient conditions, although they behaved differently in the presence of DHT.…”

Section: Resultsmentioning

confidence: 99%

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

et al. 2011

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Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.

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“…In addition to the activation of PRs via ligand-independent pathways (17,18), MAPK-dependent events may dramatically lower the EC 50 for gene activation by liganded PR (Fig. 4), ER (64), or AR (65). As all three receptors are commonly expressed in advanced breast cancers (66), inclusion of antiprogestins, antiandrogens, and the relevant kinase inhibitors to existing antiestrogen therapies may offer a more powerful treatment alternative as combination therapy.…”

Section: Ligand-independent Pr Actionsmentioning

confidence: 99%

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

et al. 2007

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Progesterone receptor (PR) action is linked to epidermal growth factor (EGF) initiated signaling pathways at multiple levels; mitogen-activated protein kinases (MAPKs) are key mediators of this important cross-talk. Herein, we probed the effects of EGF on PR function and regulation of breast cancer cell growth. EGF stimulated rapid and transient phosphorylation of PR-B Ser294 relative to persistent phosphorylation of this site induced by the synthetic progestin, R5020. EGF induced nuclear translocation and DNA binding of unliganded wild-type, but not mutant PRs containing an Ala at position 294 (S294A). However, EGF alone induced little to no PR-B transcriptional activity; S294A PR-B was transcriptionally impaired. In contrast, pretreatment of cells with EGF (30 min) significantly increased the potency and efficacy of wild-type, but not S294A PR transcriptional activity in response to progestin, and enhanced ligand-dependent downregulation of wild-type but not S294A PR. Replacement of Ser294 with aspartic acid (S294D) to mimic phosphorylation at this site decreased receptor stability and, as predicted, heightened progestin-induced transcription relative to wild-type PR-B. RT-PCR demonstrated the Ser294 phosphorylation-dependence of selected PR target genes (TGFα and HB-EGF). Surprisingly, PR-B expressing cells growing in soft agar were highly responsive to EGF or progestin, and this was further stimulated by the combination of both hormones. Cells expressing S294A PR exhibited reduced soft agar growth, and were also sensitive to R5020 alone, but failed to respond to EGF. These results suggest that PR Ser294 is an important "sensor" for growth factor inputs that affects PR function and breast cancer cell growth in the absence of progestin or in the presence of low or "sub-threshold" progestin concentrations. PR function likely contributes to breast cancer progression when EGFR family members or their ligands are overexpressed, a condition that predicts low abundance, but highly active and nuclear PR.

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Epidermal Growth Factor Increases Coactivation of the Androgen Receptor in Recurrent Prostate Cancer

Cited by 195 publications

References 91 publications

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

Osteoblast-induced EGFR/ERBB2 signaling in androgen-sensitive prostate carcinoma cells characterized by multiplex kinase activity profiling

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

Linkage of progestin and epidermal growth factor signaling: Phosphorylation of progesterone receptors mediates transcriptional hypersensitivity and increased ligand-independent breast cancer cell growth

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