Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome

Millar, Ewan K.A.; Dean, Jeffry L.; McNeil, Catriona M.; O’Toole, Sandra A.; Henshall, Susan M.; Tran, Thai H.; Lin, Jun; Quong, Andrew A.; Comstock, Clay E.S.; Witkiewicz, Agnieszka K.; Musgrove, Elizabeth A.; Rui, Hallgeir; LeMarchand, Loïc; Setiawan, Veronica Wendy; Haiman, C.A.; Knudsen, Karen E.; Sutherland, Robert L.; Knudsen, Erik S.

doi:10.1038/onc.2009.13

Cited by 75 publications

(78 citation statements)

References 36 publications

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“…The presence of CIN in this genetic subtype correlated with poor outcome. Previous studies examining the role of cyclin D1 in outcome have provided contradictory results, with some suggesting a positive correlation between cyclin D1 expression and outcome and others showing reduced survival (16,44,45). Cyclin D1 levels were induced in luminal A and B subtypes, but correlated with CIN in luminal subtype B. CIN is usually poorly tolerated by cells initiating cell death signaling.…”

Section: Discussionmentioning

confidence: 94%

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

Casimiro¹,

Crosariol²,

Loro³

et al. 2012

J. Clin. Invest.

105

123

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Chromosomal instability (CIN) in tumors is characterized by chromosomal abnormalities and an altered gene expression signature; however, the mechanism of CIN is poorly understood. CCND1 (which encodes cyclin D1) is overexpressed in human malignancies and has been shown to play a direct role in transcriptional regulation. Here, we used genome-wide ChIP sequencing and found that the DNA-bound form of cyclin D1 occupied the regulatory region of genes governing chromosomal integrity and mitochondrial biogenesis. Adding cyclin D1 back to Ccnd1 -/-mouse embryonic fibroblasts resulted in CIN gene regulatory region occupancy by the DNAbound form of cyclin D1 and induction of CIN gene expression. Furthermore, increased chromosomal aberrations, aneuploidy, and centrosome abnormalities were observed in the cyclin D1-rescued cells by spectral karyotyping and immunofluorescence. To assess cyclin D1 effects in vivo, we generated transgenic mice with acute and continuous mammary gland-targeted cyclin D1 expression. These transgenic mice presented with increased tumor prevalence and signature CIN gene profiles. Additionally, interrogation of gene expression from 2,254 human breast tumors revealed that cyclin D1 expression correlated with CIN in luminal B breast cancer. These data suggest that cyclin D1 contributes to CIN and tumorigenesis by directly regulating a transcriptional program that governs chromosomal stability. IntroductionChromosomal instability (CIN) in tumors (1-3) is characterized by an elevated rate of gain or loss of whole chromosomes (i.e., aneuploidy) and/or as structural chromosomal aberrations (i.e., translocations, deletions, and duplications). Aneuploidy is one of the most striking differences between cancer and normal cells. The molecular mechanisms inducing CIN as well as the timing of CIN in tumor progression, invasion, and metastasis is poorly understood (4, 5). Cell cycle-associated factors have been implicated in CIN, including cyclin E (6). The relative enrichment of a molecular genetic signature of CIN-related genes has been used to quantitate a CIN score (7); this signature includes AURKB (a component of the chromosomal passenger complex [CPC]), TOP2A, CENPP, MLF1IP (a component of the CENPA-NAC kinetochore complex protein), ZW10 (a kinetochore-associated mitotic checkpoint protein), and CKAP2 (a mitotic spindle-associated protein) (3) as well as the retinoblastoma (pRb) protein. Supernumerary centrosomes increase the frequency of dual attachment of 1 sister kinetochore to 2 spindle poles. Cyclin E activity promotes centrosome duplication during S phase onset. Loss of pRb can also alter centrosome number and formation of micronuclei, leading to

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Section: Discussionmentioning

confidence: 94%

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

Casimiro¹,

Crosariol²,

Loro³

et al. 2012

J. Clin. Invest.

105

123

View full text Add to dashboard Cite

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“…This finding is highly reminis- cent of the known association of elevated cyclin D1 levels with ER-positive breast cancer. 30,31 The RB transcript (Rb1) was largely unchanged across DCIS samples, indicating that the level of RB transcript levels are not a good prognosticator of RB protein expression (not shown). Therefore, to assess RB functional status, a gene expression signature of RB loss was used.…”

Section: Resultsmentioning

confidence: 99%

Association of RB/p16-Pathway Perturbations with DCIS Recurrence

Witkiewicz

Rivadeneira

Ertel

et al. 2011

The American Journal of Pathology

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The prevalence of ductal carcinoma in situ (DCIS) diagnoses has significantly increased as a result of active radiographic screening. Surgical resection and hormone and radiation therapies are effective treatments, but not all DCIS will progress to invasive breast cancer. Therefore, markers are needed to define tumors at low risk of recurrence and progression that can be treated by surgery alone rather than by adjuvant therapies. Initial analyses indicate that retinoblastoma (RB)-pathway perturbations occur at high frequency in DCIS and mirror the molecular alterations observed in invasive breast cancer. Particularly, the elevated expression of p16ink4a in DCIS was associated with loss of RB function and estrogen receptor-negative biology. Furthermore, high expression of p16ink4a in conjunction with Ki-67 was associated with increased risk of DCIS recurrence and progression to invasive disease in multivariate analyses. These data are consistent with a functional role for RB in modulating the invasive behavior of mammary epithelial cells. The tissue microenvironment is particularly relevant to the behavior of DCIS, and, surprisingly, elevated expression of p16ink4a in nonproliferative stroma was observed in a substantial fraction of cases. In this tissue compartment, p16ink4a expression was strongly associated with disease recurrence, independent of standard histopathologic features. Together, the data herein describe dual aspects of RB-pathway biology that are associated with disease recurrence through the epithelial or stromal compartment of DCIS. (Am J Pathol

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“…While cyclin D1b retains the ability to bind cyclin-dependent kinase 4 (CDK4), a potent effector of the G 1 -S phase transition, cyclin D1b is a poor catalyst of CDK4 activity (1,8). Consistent with this observation, cyclin D1b expression does not independently correlate with increased proliferative capacity in clinical specimens (5). Little insight into the underpinning mechanisms of cyclin D1b-mediated oncogenic capacity was gained from motif analyses of the transcript encoding cyclin D1b (transcript b).…”

Section: Introductionmentioning

confidence: 98%

“…Moreover, cyclin D1b has been suggested, in a limited number of model systems, to promote aggressive tumor phenotypes (4). Accordingly, emerging evidence demonstrates that preferential upregulation of the cyclin D1b isoform is tightly associated with tumor development, tumor progression, and poor outcome (5)(6)(7). Although evidence to date strongly suggests that cyclin D1b represents a gain-of-function D-cyclin variant of clinical relevance, the underlying mechanism or mechanisms by which cyclin D1b promotes protumorigenic phenotypes remain unknown.…”

Section: Introductionmentioning

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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Cyclin D1b protein expression in breast cancer is independent of cyclin D1a and associated with poor disease outcome

Cited by 75 publications

References 36 publications

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

ChIP sequencing of cyclin D1 reveals a transcriptional role in chromosomal instability in mice

Association of RB/p16-Pathway Perturbations with DCIS Recurrence

Convergence of oncogenic and hormone receptor pathways promotes metastatic phenotypes

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