Genetic regulators of large-scale transcriptional signatures in cancer

Adler, Adam S.; Lin, Meihong; Horlings, Hugo M.; Nuyten, Dimitry S.A.; Vijver, Marc J. van de; Chang, Howard Y.

doi:10.1038/ng1752

Cited by 210 publications

(218 citation statements)

References 49 publications

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“…This correlation fit with the observation that at least 10 of 20 core interactome genes are known direct MYC targets (www.myccancergene.org). It also was consistent with previous reports implicating MYC as a regulator of poor-prognosis signature expression in breast cancer (18)(19)(20)(21)(22). Taken together, this evidence raised the hypothesis that MYC, which is downstream of the ERα, ERBB2, EGFR, and AR pathways, may act as a common transcriptional regulator for expression of the 13 different poor-outcome signatures that we studied.…”

Section: Resultssupporting

confidence: 80%

MYC regulation of a “poor-prognosis” metastatic cancer cell state

Wolfer

Wittner

Irimia

et al. 2010

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

156

109

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Gene expression signatures are used in the clinic as prognostic tools to determine the risk of individual patients with localized breast tumors developing distant metastasis. We lack a clear understanding, however, of whether these correlative biomarkers link to a common biological network that regulates metastasis. We find that the c-MYC oncoprotein coordinately regulates the expression of 13 different "poor-outcome" cancer signatures. In addition, functional inactivation of MYC in human breast cancer cells specifically inhibits distant metastasis in vivo and invasive behavior in vitro of these cells. These results suggest that MYC oncogene activity (as marked by "poor-prognosis" signature expression) may be necessary for the translocation of poor-outcome human breast tumors to distant sites.

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Section: Resultssupporting

confidence: 80%

MYC regulation of a “poor-prognosis” metastatic cancer cell state

Wolfer

Wittner

Irimia

et al. 2010

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

156

109

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“…Significant correlations between the expression profiles of under-and/or overexpressed sets and E2F1, IRF1, IRF7 and SP1 were identified relative to randomly selected equivalent gene sets (Po10 À3 ) (Figure 4c, top left panels show results for E2F1). In addition, the overexpressed set showed coexpression with MYC (Figure 4c, top right panels), which is consistent with TFBSs predictions (Figure 4a) and the role of MYC regulation of poor outcome signatures (Adler et al, 2006;Wolfer et al, 2010). Significant coexpression was also observed for ZFX (Figure 4c, bottom left panels), although with an opposite pattern that suggests a differential effect on transcriptional regulation during acquired resistance.…”

Section: Effect Of 17be2 Through Erasupporting

confidence: 84%

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

et al. 2010

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Endocrine therapies targeting the proliferative effect of 17b-estradiol through estrogen receptor a (ERa) are the most effective systemic treatment of ERa-positive breast cancer. However, most breast tumors initially responsive to these therapies develop resistance through molecular mechanisms that are not yet fully understood. The longterm estrogen-deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibitors in postmenopausal women. To elucidate this resistance, genomic, transcriptomic and molecular data were integrated into the time course of MCF7-LTED adaptation. Dynamic and widespread genomic changes were observed, including amplification of the ESR1 locus consequently linked to an increase in ERa. Dynamic transcriptomic profiles were also observed that correlated significantly with genomic changes and were predicted to be influenced by transcription factors known to be involved in acquired resistance or cell proliferation (for example, interferon regulatory transcription factor 1 and E2F1, respectively) but, notably, not by canonical ERa transcriptional function. Consistently, at the molecular level, activation of growth factor signaling pathways by EGFR/ERBB/AKT and a switch from phospho-Ser118 (pS118)-to pS167-ERa were observed during MCF7-LTED adaptation. Evaluation of relevant clinical settings identified significant associations between MCF7-LTED and breast tumor transcriptome profiles that characterize ERa-negative status, early response to letrozole and tamoxifen, and recurrence after tamoxifen treatment. In accordance with these profiles, MCF7-LTED cells showed increased sensitivity to inhibition of FGFR-mediated signaling with PD173074. This study provides mechanistic insight into acquired resistance to endocrine therapies of breast cancer and highlights a potential therapeutic strategy.

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“…JAB1 regulates cellular signaling such as the AP-1 and MAPK pathways (Chamovitz and Segal, 2001;Bech-Otschir et al, 2002;Lue et al, 2006). JAB1 is overexpressed in many tumor entities and has been indirectly linked to prosurvival effects in several carcinomas, that is via p27 (Tomoda et al, 1999;Chamovitz and Segal, 2001;Adler et al, 2006;Osoegawa et al, 2006), but does not directly regulate PI3K/Akt signaling. In line with findings, suggesting a JAB1/c-Myc-based mechanism underlying JAB1's role in breast cancer development, we have found no obvious correlation between JAB1 levels in several breast cancer cell lines and their Akt activation status.…”

Section: Discussionmentioning

confidence: 99%