An E2F1-Dependent Gene Expression Program that Determines the Balance between Proliferation and Cell Death

Hallstrom, Timothy C.; Mori, Seiichi; Nevins, Joseph R.

doi:10.1016/j.ccr.2007.11.031

Cited by 239 publications

(221 citation statements)

References 52 publications

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“…The top 66% (451 probes) of variable probes were then used to cluster the BFRM normalized Mas5 formatted gene expression data using complete linkage hierarchical clustering. Previously identified intrinsic subtypes were identified and the expression characteristics of each subtype were found to be consistent with previously published studies (4,13,6). Specifically, the HER2+ expression cluster was found to show high expression of genes in the 17q21 amplicon including HER2/ERBB2 and GRB7.…”

Section: Methodssupporting

confidence: 71%

“…Other relationships, not necessarily anticipated from past work, are also evident in this analysis including coactivation of E2F1 and PI3K pathways together with β-catenin. Interestingly, E2F1 is known to act as a signal for p53-dependent apoptosis, which is negated by PI3K activity (13). Finally, other patterns are evident including AKT/p63/ SRC as well as EGFR/TGFβ and STAT3/TNFα.…”

Section: Patterns Of Pathway Activity Characterize the Diversity Of Bmentioning

confidence: 94%

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A pathway-based classification of human breast cancer

Gatza

Lucas²,

Barry³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The hallmark of human cancer is heterogeneity, reflecting the complexity and variability of the vast array of somatic mutations acquired during oncogenesis. An ability to dissect this heterogeneity, to identify subgroups that represent common mechanisms of disease, will be critical to understanding the complexities of genetic alterations and to provide a framework to develop rational therapeutic strategies. Here, we describe a classification scheme for human breast cancer making use of patterns of pathway activity to build on previous subtype characterizations using intrinsic gene expression signatures, to provide a functional interpretation of the gene expression data that can be linked to therapeutic options. We show that the identified subgroups provide a robust mechanism for classifying independent samples, identifying tumors that share patterns of pathway activity and exhibit similar clinical and biological properties, including distinct patterns of chromosomal alterations that were not evident in the heterogeneous total population of tumors. We propose that this classification scheme provides a basis for understanding the complex mechanisms of oncogenesis that give rise to these tumors and to identify rational opportunities for combination therapies.

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Section: Methodssupporting

confidence: 71%

Section: Patterns Of Pathway Activity Characterize the Diversity Of Bmentioning

confidence: 94%

A pathway-based classification of human breast cancer

Gatza

Lucas²,

Barry³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

306

372

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show abstract

“…up-regulates the expression of SVV, most likely through a previously reported direct interaction with the SVV promoter, 42,43 thereby contributing to the invasive potential of BC cells.…”

Section: Discussionmentioning

confidence: 92%

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

Abdraboh

Gaur

Hollenbach

et al. 2011

The American Journal of Pathology

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The hyaluronan (HA) receptor CD44 plays an essential role in cell-cell or cell-extracellular matrix communications and is a bioactive signal transmitter. Although a number of studies have described the function of CD44 in breast cancer (BC) metastasis, the underlying mechanisms have yet to be determined. By using a validated tetracycline-off-regulated CD44 expression system in the MCF-7 cell line combined with microarray analysis, we identified survivin (SVV) as a potential downstream transcriptional target of CD44. To test the hypothesis that SVV underpins CD44-promoted BC cell invasion, we combined molecular and pharmacologic approaches and showed that CD44 induction increased SVV expression levels, which in turn promotes BC cell invasion. Further, clinical analysis of breast tissue samples showed that SVV expression patterns paralleled those of the standard form of CD44 during breast tumor progression. More interestingly, we identified the PI3K/E2F1 pathway as a potential molecular link between HA/CD44 activation and SVV transcription. In addition to identifying SVV as a target for HA/CD44 signaling, this investigation provides a better understanding of the molecular mechanisms that underpin the novel function of SVV in breast cancer metastasis. Breast cancer (BC) is the most common cancer and the second most common cause of cancer-related deaths in women in the United States, with more than 175,000 women being diagnosed annually. 1,2 In the later stages of progression, BC cells metastasize from the original tumor site and travel through the vasculature to distant organs such as liver, lungs, brain, and bone. [2][3][4][5] Although the involvement of cell adhesion molecules in cancer development, progression, and metastasis has been established and discussed extensively in the literature, the mechanisms underlying their implication is still nascent. 6 -9 The hyaluronan (HA) receptor CD44, a multistructural and multifunctional cell adhesion molecule involved in cell-cell and cell-extracellular matrix interactions, functions as a bioactive signaling transmitter involved in a variety of cellular responses, including lymphocyte homing, hematopoiesis, inflammation, tumorigenesis, angiogenesis, and metastasis. 10 -13 The CD44 -HA complex initiates a series of intracellular signaling events that lead to migration, adhesion, invasion, proliferation, and differentiation of a variety of cells. The transduction of HA/CD44 signaling can occur through various mechanisms including the following: i) HA binding to CD44 can initiate the extracellular clustering of CD44, resulting in the activation of downstream kinases, 14 ii) CD44 can serve as a co-receptor physically associated with other cell signaling receptors, [15][16][17][18] iii) CD44 can serve as a docking protein for pericellular or cytoplasmic proteins, 19,20 and iv) the transmembrane domain of CD44 can be cleaved, allowing the translocation of the cytoplasmic domain to the nucleus, where it functions as a transcription factor regulating the expression of target gen...

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“…Activation of AMPK induces p53-dependent apoptotic cell death in response to energetic stress [37]. Moreover, AMPK activation with AICAR further enhances E2F1-mediated apoptosis [38]. All these studies suggested that AMPK activation could play a pro-apoptotic role in different types of cells.…”

Section: Discussionmentioning

confidence: 95%

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

García-García¹,

Fumarola²,

Navaratnam³

et al. 2010

Biochemical Pharmacology

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The tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a TNF superfamily member that is being considered as a new strategy in anticancer therapy because of its ability to induce apoptosis, alone or in combination with other stimuli, in many cancer cells. AMPactivated protein kinase (AMPK) is an evolutionarily conserved key regulator of cellular energy homeostasis that protects the cell from energy depletion and stress by activating several biochemical pathways that lead to the conservation, as well as generation, of ATP.Here we report that a number of AMPK activators, including the small molecule activator A-769662, markedly sensitize TRAIL-resistant breast cancer cells to TRAIL-induced apoptosis.However, silencing AMPKα1 expression with siRNA or over-expression of DN-AMPKα1 does not inhibit AICAR, glucose deprivation, phenformin or A-769662-induced sensitization to TRAIL. Furthermore, the expression of constitutively active AMPK subunits does not sensitize resistant breast cancer cells to TRAIL-induced apoptosis. The cellular FLICEinhibitory proteins (cFLIP L and cFLIP S ) were significantly down-regulated following exposure to AMPK activators through an AMPK-independent mechanism. Furthermore, in cells over-expressing cFLIP L , sensitization to TRAIL by AMPK activators was markedly reduced. In summary, our results indicate that AMPK activators facilitate the activation by TRAIL of an apoptotic cell death program through a mechanism independent of AMPK and dependent on the down-regulation of cFLIP levels.

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An E2F1-Dependent Gene Expression Program that Determines the Balance between Proliferation and Cell Death

Cited by 239 publications

References 52 publications

A pathway-based classification of human breast cancer

A pathway-based classification of human breast cancer

Survivin Is a Novel Target of CD44-Promoted Breast Tumor Invasion

AMPK-independent down-regulation of cFLIP and sensitization to TRAIL-induced apoptosis by AMPK activators

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