pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia

Simin, Karl; Wu, H.; Lu, Lucy; Pinkel, Dan; Albertson, Donna G.; Cardiff, Robert D.; Dyke, Terry Van

doi:10.1371/journal.pbio.0020022

Cited by 58 publications

(54 citation statements)

References 55 publications

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“…Although our data cannot absolutely exclude this explanation, they argue against it. The high frequency of p53 inactivation in our study together with that seen with other examples of mammary tumorigenic synergy -for example, p53 þ /À BRCA2 À/À mice (Jonkers et al, 2001) and in a p53 þ /À conditional Rb-inactivated mouse (Simin et al, 2004) support the notion that inactivation of p53, rather than haploinsufficiency, is a key event in mammary tumorigenesis in mice although a systematic study in spontaneous mammary lesions of mice is needed. This is supported by work on human breast cancers reporting that overexpression of cyclin E is associated with specific mutation types in p53 (Lindahl et al, 2004).…”

Section: Discussionsupporting

confidence: 80%

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

et al. 2006

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Deregulation of cyclin E expression and/or high levels have been reported in a variety of tumors and have been used as indicators of poor prognosis. Although the role that cyclin E plays in tumorigenesis remains unclear, there is evidence that it confers genomic instability when deregulated in cultured cells. Here we show that deregulated expression of a hyperstable allele of cyclin E in mice heterozygous for p53 synergistically increases mammary tumorigenesis more than that in mice carrying either of these markers individually. Most tumors and tumor-derived cell lines demonstrated loss of p53 heterozygosity. Furthermore, this tumor susceptibility is related to the number of times the transgene is induced indicating that it is directly attributable to the expression of the cyclin E transgene. An indirect assay indicates that loss of p53 function is an early event occurring in the mammary epithelia of midlactation mammary glands in which cyclin E is deregulated long before evidence of malignancy. These data support the hypothesis that deregulated expression of cyclin E stimulates p53 loss of heterozygosity by promoting genomic instability and provides specific evidence for this in vivo. Cyclin E deregulation and p53 loss are characteristics often observed in human breast carcinoma.

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Section: Discussionsupporting

confidence: 80%

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

et al. 2006

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“…Therefore, it was surprising that the histopathology and expression profiles of the Brg1 þ /À mammary tumors were not more similar to Wap-T121 mammary tumors where the function of RB and the other two pocket proteins (p107 and p130) are perturbed (Simin et al, 2004). To investigate whether Brg1 and Rb genetically interact in vivo, we introduced the Brg1 null mutation onto an Rb mutant background.…”

Section: Resultsmentioning

confidence: 99%

Characterization of mammary tumors from Brg1 heterozygous mice

et al. 2007

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Mammalian SWI/SNF-related complexes have been implicated in cancer based on some of the subunits physically interacting with retinoblastoma (RB) and other proteins involved in carcinogenesis. Additionally, several subunits are mutated or not expressed in tumor-derived cell lines. Strong evidence for a role in tumorigenesis in vivo, however, has been limited to SNF5 mutations that result primarily in malignant rhabdoid tumors (MRTs) in humans and MRTs as well as other sarcomas in mice. We previously generated a null mutation of the Brg1 catalytic subunit in the mouse and reported that homozygotes die during embryogenesis. Here, we demonstrate that Brg1 heterozygotes are susceptible to mammary tumors that are fundamentally different than Snf5 tumors. First, mammary tumors are carcinomas not sarcomas. Second, Brg1 þ /À tumors arise because of haploinsufficiency rather than loss of heterozygosity. Third, Brg1 þ /À tumors exhibit genomic instability but not polyploidy based on array comparative genomic hybridization results. We monitored Brg1 þ /À , Brm À/À double-mutant mice but did not observe any tumors resembling those from Snf5 mutants, indicating that the Brg1 þ /À and Snf5 þ /À tumor phenotypes do not differ simply because Brg1 has a closely related paralog whereas Snf5 does not. These findings demonstrate that BRG1 and SNF5 are not functionally equivalent but protect against cancer in different ways. We also demonstrate that Brg1 þ /À mammary tumors have relatively heterogeneous gene expression profiles with similarities and differences compared to other mouse models of breast cancer. The Brg1 þ /À expression profiles are not particularly similar to mammary tumors from Wap-T121 transgenic line where RB is perturbed. We were also unable to detect a genetic interaction between the Brg1 þ /À and Rb þ /À tumor phenotypes. These latter findings do not support a BRG1-RB interaction in vivo. IntroductionMuch work has focused on the role of mammalian SWI/ SNF-related complexes in cancer. SWI/SNF-related subunits physically interact with a number of proteins encoded by tumor-suppressor genes and proto-oncogenes (Muchardt and Yaniv, 2001;Roberts and Orkin, 2004). For example, BRM and BRG1 bind retinoblastoma (RB) and are required to repress the activity of E2F1, inhibit the transcription of cyclins A and E and mediate G 1 cell-cycle arrest in vitro. BRG1 and SNF5 can also act upstream of RB by activating the expression of several cyclin-dependent kinase inhibitors (p15 INK4b , p16 INK4A or p21 CIP1/WAF1 ), which leads to the inhibition of CDK2 and CDK4 and accumulation of the hypophosphorylated form of RB that mediates G 1 arrest.In addition to being associated with cancer-related proteins, the BRM, BRG1, SNF5, BAF155 and BAF250 subunits are mutated or not expressed in various tumor-derived cell lines (Muchardt and Yaniv, 2001). When tumor-derived cell lines are cultured, however, deletions and epigenetic alterations are selected for and accumulate. Because of this caveat, it is crucial to identify and characterize mu...

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“…This indicates that also in vivo, tumor development by abrogation of the pRB pathway can be accelerated by partial ablation of the p53 pathway. Moreover, various mouse tumor models have been generated by combined deletion of p53 and Rb, including tumors of the lung (29), central nervous system (28), breast (42), and pineal and pituitary glands (45). Finally, simultaneous mutations in both pathways have been found in a variety of mouse and human tumor samples (4,30).…”

Section: Discussionmentioning

confidence: 99%

Anchorage-Independent Growth of Pocket Protein-Deficient Murine Fibroblasts Requires Bypass of G₂ Arrest and Can Be Accomplished by Expression of TBX2

Vormer

Foijer

Wielders

et al. 2008

Molecular and Cellular Biology

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Mouse embryonic fibroblasts (MEFs) deficient for pocket proteins (i.e., pRB/p107-, pRB/p130-, or pRB/ p107/p130-deficient MEFs) have lost proper G 1 control and are refractory to Ras V12 -induced senescence. However, pocket protein-deficient MEFs expressing Ras V12 were unable to exhibit anchorage-independent growth or to form tumors in nude mice. We show that depending on the level of pocket proteins, loss of adhesion induces G 1 and G 2 arrest, which could be alleviated by overexpression of the TBX2 oncogene. TBX2-induced transformation occurred only in the absence of pocket proteins and could be attributed to downregulation of the p53/p21 CIP1 pathway. Our results show that a balance between the pocket protein and p53 pathways determines the level of transformation of MEFs by regulating cyclin-dependent kinase activities. Since transformation of human fibroblasts also requires ablation of both pathways, our results imply that the mechanisms underlying transformation of human and mouse cells are not as different as previously claimed.Deregulation of the pRB tumor suppressor pathway is a frequent event in the development of cancer (18, 31). pRB and its close homologs p107 and p130 comprise the family of socalled pocket proteins and are widely known for their role in cell cycle regulation, especially during G 1 phase. In their active, hypophosphorylated form, pocket proteins restrict cell cycle progression by binding to E2F transcription factors. E2F-pocket protein complex formation inhibits the expression of E2F target genes both by blocking E2F's ability to induce transcription and by active repression. As a result, initiation of S phase is inhibited. Upon cell cycle stimulation, cyclin D-CDK4/6 (cyclin-dependent kinase 4 or 6) and cyclin E-CDK2 complexes are activated and hyperphosphorylate the pocket proteins, resulting in liberation and activation of E2F transcription factors and initiation of S phase. Further cell cycle progression requires cyclin A-CDK1/2 activity in S phase and cyclin A-CDK1/2 and cyclin B1-CDK1 activities in G 2 /M phase. The activity of cyclin-CDK complexes can be inhibited by the INK4a (inhibitor of cyclin-dependent kinase 4a) and the CIP/KIP families of CDK inhibitors (reviewed in reference 2).Consistent with a role for pocket proteins in G 1 control, we and others have shown that complete ablation of pocket proteins in mouse embryonic fibroblasts (MEFs) abrogated G 1 arrest in response to growth-inhibitory signals, such as cell-cell contact, growth factor depletion, and DNA damage. Additionally, upon prolonged culturing or expression of constitutively active Ras (Ras V12 ), wild-type MEFs arrested in G 1 and displayed hallmarks of senescence, while MEFs deficient for both pRb and p107 or both pRb and p130 (double-knockout [DKO] MEFs) or all three pocket proteins (triple-knockout [TKO] MEFs) were refractory to replicative and Ras V12 -induced senescence (6,7,32,38). Similar to ablation of pocket proteins, ablation of the tumor suppressor p53 or its upstream regulator p19 ARF also byp...

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pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia

Cited by 58 publications

References 55 publications

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Characterization of mammary tumors from Brg1 heterozygous mice

Anchorage-Independent Growth of Pocket Protein-Deficient Murine Fibroblasts Requires Bypass of G₂ Arrest and Can Be Accomplished by Expression of TBX2

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pRb Inactivation in Mammary Cells Reveals Common Mechanisms for Tumor Initiation and Progression in Divergent Epithelia

Cited by 58 publications

References 55 publications

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

Characterization of mammary tumors from Brg1 heterozygous mice

Anchorage-Independent Growth of Pocket Protein-Deficient Murine Fibroblasts Requires Bypass of G2 Arrest and Can Be Accomplished by Expression of TBX2

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Anchorage-Independent Growth of Pocket Protein-Deficient Murine Fibroblasts Requires Bypass of G₂ Arrest and Can Be Accomplished by Expression of TBX2