Androgen receptor corepressors and prostate cancer

Burd, Craig J.; Morey, Lisa M.; Knudsen, Karen E.

doi:10.1677/erc.1.01115

Cited by 69 publications

(59 citation statements)

References 125 publications

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“…It has been previously shown through in vitro studies that cyclin D1 can influence androgen-dependent prostate cancer cell proliferation through its dual ability to modulate both CDK4 and AR activity (Petre-Draviam et al, 2005;Burd et al, 2006a). To elucidate further the role of cyclin D1 in prostate cancer, primary human prostate cancer specimens were utilised to assess the influence of cyclin D1 expression and localisation on PSA levels and proliferation index.…”

Section: Discussionmentioning

confidence: 99%

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Impact of differential cyclin D1 expression and localisation in prostate cancer

et al. 2007

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Cyclin D1 is a critical regulator of androgen-dependent transcription and cell cycle progression in prostate cancer cells. Despite the influence of D-type cyclins on prostate cancer proliferation, few studies have examined the expression of cyclin D1 in localised tumours or challenged its relevance to disease progression. Cyclin D1 status was characterised using immunohistochemistry in 38 non-neoplastic prostate samples, 138 primary human prostate carcinomas, and three lymph node metastatic specimens. Relevance of cyclin D1 to preoperative prostate-specific antigen (PSA) levels, Ki-67 index, and p21 Cip1 status was also examined. Cyclin D1-positive phenotype was increased in primary carcinoma compared to non-neoplastic tissue, and was evident in all lymph node metastases cases. Interestingly, at least three distinct localisation patterns were observed in the cyclin D1-positive cohort, wherein cytoplasmic localisation was identified in a large fraction, and this pattern was predominant in lower grade tumours. Relevance of altered cyclin D1 status was observed, wherein cyclin D1-positive tumours were associated with low preoperative PSA levels, consistent with in vitro reports that cyclin D1 may alter the expression of this tumour marker. Moreover, tumours with predominantly cytoplasmic cyclin D1 showed the lowest Ki-67 index, whereas nuclear cyclin D1 was associated with higher grade, elevated Ki-67, and increased nuclear p21 Cip1 . These data demonstrate that differential cyclin D1 status may influence clinicopathological parameters, and reveal new insight as to the regulation and potential consequence of cyclin D1 expression in prostate cancer.

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Section: Discussionmentioning

confidence: 99%

“…Cyclin D1 has the potential to regulate both cellular proliferation and AR-dependent transcription in prostate cancer cells (Burd et al, 2006a). Therefore, a link between the expression of cyclin D1 and PSA, an AR target gene, was examined.…”

Section: Cyclin D1 Status Is Inversely Associated With Psa Levelsmentioning

confidence: 99%

Impact of differential cyclin D1 expression and localisation in prostate cancer

et al. 2007

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“…While previous biochemical analyses have demonstrated that cyclin D1b and AR maintain the ability to interact (19,30), it remained unclear if such complexes exist on chromatin. Thus, chromatin-tethering-coupled immunoprecipitation assays, which have previously been shown to distinguish between nuclear and chromatin-associated complexes (31), were performed.…”

Section: Cyclin D1b Induces a Unique Gene Expression Program Associatmentioning

confidence: 99%

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Augello¹,

Burd²,

Birbe³

et al. 2012

J. Clin. Invest.

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Cyclin D1b is a splice variant of the cell cycle regulator cyclin D1 and is known to harbor divergent and highly oncogenic functions in human cancer. While cyclin D1b is induced during disease progression in many cancer types, the mechanisms underlying cyclin D1b function remain poorly understood. Herein, cell and human tumor xenograft models of prostate cancer were utilized to resolve the downstream pathways that are required for the protumorigenic functions of cyclin D1b. Specifically, cyclin D1b was found to modulate the expression of a large transcriptional network that cooperates with androgen receptor (AR) signaling to enhance tumor cell growth and invasive potential. Notably, cyclin D1b promoted AR-dependent activation of genes associated with metastatic phenotypes. Further exploration determined that transcriptional induction of SNAI2 (Slug) was essential for cyclin D1b-mediated proliferative and invasive properties, implicating Slug as a critical driver of disease progression. Importantly, cyclin D1b expression highly correlated with that of Slug in clinical samples of advanced disease. In vivo analyses provided strong evidence that Slug enhances both tumor growth and metastatic phenotypes. Collectively, these findings reveal the underpinning mechanisms behind the protumorigenic functions of cyclin D1b and demonstrate that the convergence of the cyclin D1b/AR and Slug pathways results in the activation of processes critical for the promotion of lethal tumor phenotypes.

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“…These mechanisms imply the existence of an active androgen receptor pathway in most cases. These mechanisms include: (a) androgen receptor gene amplification (6,7); (b) changes in ligand specificity due to mutations in the ligand-binding domain of the androgen receptor (6,7); (c) ligand-independent activation of the androgen receptor due to increased MAPK signaling (6); and (d) alteration in the balance and/or recruitment of androgen receptor coactivators and corepressors (8,9). The role of the androgen receptor pathway in the osteoblastic progression of prostate cancer is unknown.…”

Section: Introductionmentioning

confidence: 99%

Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

Li¹,

Mathew²,

Yang³

et al. 2008

J. Clin. Invest.

145

228

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In prostate cancer, androgen blockade strategies are commonly used to treat osteoblastic bone metastases. However, responses to these therapies are typically brief, and the mechanism underlying androgen-independent progression is not clear. Here, we established what we believe to be the first human androgen receptor-negative prostate cancer xenografts whose cells induced an osteoblastic reaction in bone and in the subcutis of immunodeficient mice. Accordingly, these cells grew in castrated as well as intact male mice. We identified FGF9 as being overexpressed in the xenografts relative to other bone-derived prostate cancer cells and discovered that FGF9 induced osteoblast proliferation and new bone formation in a bone organ assay. Mice treated with FGF9-neutralizing antibody developed smaller bone tumors and reduced bone formation. Finally, we found positive FGF9 immunostaining in prostate cancer cells in 24 of 56 primary tumors derived from human organ-confined prostate cancer and in 25 of 25 bone metastasis cases studied. Collectively, these results suggest that FGF9 contributes to prostate cancer-induced new bone formation and may participate in the osteoblastic progression of prostate cancer in bone. Androgen receptor-null cells may contribute to the castration-resistant osteoblastic progression of prostate cancer cells in bone and provide a preclinical model for studying therapies that target these cells.

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Androgen receptor corepressors and prostate cancer

Cited by 69 publications

References 125 publications

Impact of differential cyclin D1 expression and localisation in prostate cancer

Impact of differential cyclin D1 expression and localisation in prostate cancer

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

Androgen receptor–negative human prostate cancer cells induce osteogenesis in mice through FGF9-mediated mechanisms

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