A Mechanism of Cyclin D1 Action Encoded in the Patterns of Gene Expression in Human Cancer

Abstract

Here we describe how patterns of gene expression in human tumors have been deconvoluted to reveal a mechanism of action for the cyclin D1 oncogene. Computational analysis of the expression patterns of thousands of genes across hundreds of tumor specimens suggested that a transcription factor, C/EBPbeta/Nf-Il6, participates in the consequences of cyclin D1 overexpression. Functional analyses confirmed the involvement of C/EBPbeta in the regulation of genes affected by cyclin D1 and established this protein as an indispensable effector of a potentially important facet of cyclin D1 biology. This work demonstrates that tumor gene expression databases can be used to study the function of a human oncogene in situ.

Cyclin D1: polymorphism, aberrant splicing and cancer risk

“…Evidence for CDK-independent functions was first observed in clinical samples, wherein breast cancers overexpressing cyclin D1 failed to show enhanced proliferation rates, and control of the RB pathway was retained (Oyama et al, 1998;Lamb et al, 2003). In addition, B-cell lymphomas overexpressing cyclin D1 retained RB in its activated state (Zukerberg et al, 1996).…”

“…Subsequent studies strikingly demonstrated that cyclin D1 is a modifier of gene transcription, and that this function of cyclin D1 has important implications in tumor biology. Specifically, cyclin D1 has been shown to regulate a number of sequence-specific transcription factors, including C/EBPb (Lamb et al, 2003), STAT3 (Bienvenu et al, 2001), DMP1 (Inoue and Sherr, 1998), and BETA2/NeuroD (Ratineau et al, 2002). The largest class of transcription factors regulated by cyclin D1 belong to the nuclear receptor superfamily, and include the estrogen receptor (Zwijsen et al, 1998;Lamb et al, 2000), androgen receptor (Knudsen et al, 1999;Reutens et al, 2001;Petre et al, 2002;Burd et al, 2005), thyroid hormone receptor (Pibiri et al, 2001), and peroxisome proliferator activated receptor-g (Qin et al, 2003).…”

“…Specifically, transcriptional activation is associated with an LxxLL motif that is important for coactivator recruitment (Zwijsen et al, 1998;McMahon et al, 1999), whereas transcriptional repression is associated with the presence of a repressor domain for selected transcription factors (Petre-Draviam et al, 2005). The biological significance of the cyclin D1 transcriptional regulatory function was solidified in a large scale, comprehensive analysis of genes deregulated in breast cancer specimens (Lamb et al, 2003). This study unexpectedly revealed that cyclin D1 overexpression does not disrupt the RB function in breast cancer, and the cellular changes associated with cyclin D1 overexpression were not attributed to alterations in cell cycle.…”

A gene transcription signature of the Akt/mTOR pathway in clinical breast tumors

“…Although preclinical and early clinical results have been encouraging, there is a real need for biomarkers for selecting those patients who may benefit most from anti-mTOR therapy (Morgensztern and McLeod, 2005;Johnston, 2006). Recent studies have defined mRNA expression patterns, or 'signatures', of deregulation of specific pathways -including Myc, Ras, cyclin D1, b-catenin, HER2/neu, epidermal growth factor receptor and mitogen-activated protein kinasein human cancer (Lamb et al, 2003;Sweet-Cordero et al, 2005;Bild et al, 2006;Creighton et al, 2006a, b). Preclinical studies indicate that these oncogenic signatures could be used as a guide for targeted therapies (Bild et al, 2006).…”

Conditional ablation of C/EBPβ demonstrates its keratinocyte-specific requirement for cell survival and mouse skin tumorigenesis

“…C/EBPb is highly expressed in colorectal tumors (Rask et al, 2000) and is associated with ovarian tumor progression (Sundfeldt et al, 1999). Furthermore, C/EBPb can interact with cyclin D1 and appears to be important for the unique pattern of altered gene expression in human cancers that overexpress cyclin D1 (Lamb et al, 2003).…”