Impact of differential cyclin D1 expression and localisation in prostate cancer

Abstract

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.

Cyclin D3 action in androgen receptor regulation and prostate cancer

“…Here, we showed that cyclin D3 localization is largely cytoplasmic in low-grade tumors and as tumor grade increases, total cyclin D3 expression is diminished. This profile is distinct from recent analyses of cyclin D1 expression, where although a large fraction of tumors score negative for cyclin D1, increased cytoplasmic expression was observed in a subset of tumors, and some nuclear expression is noted in higher grades (Comstock et al, 2007). Total cyclin D3 expression is inversely correlated with Ki-67, whereas nuclear cyclin D1 corresponds with higher Ki-67.…”

“…Hematoxylin and eosin staining, immunohistochemical staining for cyclin D3 and Ki-67, scoring, analyses and images were performed as previously described (Wetherill et al, 2006;Comstock et al, 2007).…”

“…These observations led to the hypothesis that while androgen induction of cyclin D1 leads to CDK4 activation and promotes G1-S progression (Knudsen et al, 1998;Xu et al, 2006), accumulated cyclin D1 regulates this by binding to AR and suppressing subsequent signaling (Knudsen et al, 1999;Reutens et al, 2001;Petre et al, 2002). Recently, it was observed that this process is disrupted in PCa through alternative splicing of cyclin D1 (which compromises AR regulation), or through aberrant cyclin D1 expression (loss or cytoplasmic sequestration) (Burd et al, 2006;Comstock et al, 2007). Thus, alterations in cyclin D1 are at least one mechanism to promote AR activity in PCa progression.…”

The Complex Role of AR Signaling After Cytotoxic Insult: Implications for Cell Cycle Based Chemotherapeutics

“…[31][32][33] Disruption in this process has been associated with unchecked AR activity and has been found to occur at multiple levels in human tumors. [34][35][36] In addition, CDK6 negates the ability of cyclin D1 to suppress AR function, and can serve to heighten AR activity independent of it skinase function. 37 In G 2 , CDK1 activity has been shown to promote AR phosphorylation and stabilization, resulting in increased AR activity.…”

The role of SPARC in the TRAMP model of prostate carcinogenesis and progression

“…SPARC in prostate cancer N Said et al positive correlation with prostate cancer metastasis (Comstock et al, 2007). Conversely, upregulation of p21 Cip and/or p27 Kip inhibits the activity of most cyclin/ cyclin-dependent kinase complexes, causing growth inhibition in prostate cancer (Roy et al, 2007).…”