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

Wolfer, Anita; Wittner, Ben S.; Irimia, Daniel; Flavin, Richard; Lupien, Mathieu; Gunawardane, Ruwanthi N.; Meyer, Clifford A.; Lightcap, Eric S.; Tamayo, Pablo; Liu, X. Shirley; Shioda, Toshi; Toner, Mehmet; Loda, Massimo; Brown, Myles; Brugge, Joan S.; Ramaswamy, Sridhar

doi:10.1073/pnas.0914203107

Cited by 153 publications

(119 citation statements)

References 43 publications

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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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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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“…1B and Fig. S1A) (4,8). However, these cells expressed very low levels of critical proliferation proteins (e.g., MKI67 low , MCM2 low , CDC6 low , GMNN low , AURKA low , PLK1 low ) and histone marks (i.e., H3S10ph low , H3K4me2 low , H3K9me2 low , H3K27me3 low , H4K12ac low , H4K16ac low ) that are suppressed in noncycling cells ( Fig.…”

Section: G0-like Cancer Cells In Vitromentioning

confidence: 99%

Asymmetric cancer cell division regulated by AKT

Dey‐Guha

Wolfer

Yeh

et al. 2011

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

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Human tumors often contain slowly proliferating cancer cells that resist treatment, but we do not know precisely how these cells arise. We show that rapidly proliferating cancer cells can divide asymmetrically to produce slowly proliferating "G0-like" progeny that are enriched following chemotherapy in breast cancer patients. Asymmetric cancer cell division results from asymmetric suppression of AKT/PKB kinase signaling in one daughter cell during telophase of mitosis. Moreover, inhibition of AKT signaling with smallmolecule drugs can induce asymmetric cancer cell division and the production of slow proliferators. Cancer cells therefore appear to continuously flux between symmetric and asymmetric division depending on the precise state of their AKT signaling network. This model may have significant implications for understanding how tumors grow, evade treatment, and recur.quiescence | epigenetics | cell signaling | drug resistance T umors generally evolve through years of mutation and clonal selection (1). This favors the outgrowth of rapidly proliferating cancer cells over time. However, even advanced tumors contain many cancer cells that appear to be proliferating slowly (2). This proliferative heterogeneity correlates closely with time to clinical detection, growth, metastasis, and treatment response across all tumor types, but we still do not understand clearly how it arises. The rate of mammalian cell proliferation is generally determined by the time spent in G1 of the cell cycle. Critical genetic and epigenetic changes within cancer cells accelerate G1 transit, whereas a suboptimal microenvironment with imbalance of growth factors, nutrients, or oxygen can slow G1 progression (3). Therefore, individual cancer cells within a tumor are thought to vary significantly in their proliferative rate depending on the precise balance of these intrinsic and extrinsic factors. Interestingly, however, many tumor-derived cancer cell lines also produce slowly proliferating cells. These established lines have many acquired mutations that drive cell proliferation. They have also been grown ex vivo for years in a stable microenvironment to promote unbridled proliferation. These factors ought to favor a strong purifying selection against slow proliferators. We worked to understand how slowly proliferating cells seem to arise paradoxically in cancer cell lines.Results G0-Like Cancer Cells in Vitro. We began by studying MCF7, a highly proliferative, aneuploid, ER + /HER2 − human breast cancer cell line. This line displays significant proliferative heterogeneity despite mutations in CDKN2A and PIK3CA that cooperatively drive cell-cycle progression (4). We first hypothesized that slowly proliferating MCF7 cells might produce low levels of reactive oxygen species (ROS). This hypothesis was based on previous observations that slowly cycling hematopoietic, neural, and breast adult stem cells and cancer stem cells produce low levels of ROS (5-7). We stained MCF7 cells with 5-(and-6)chloromethyl 1-2′,7′-dichlorohydrofluorescein diacet...

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“…For example, FOXP3 directly represses the ERBB2 and SKP2 oncogenes while maintaining the expression of the p21 tumour suppressor in the breast epithelium (Zuo et al, 2007a, b;Liu et al, 2009). In prostate cells, FOXP3 has also been shown to directly repress c-myc transcription , an oncogene frequently overexpressed in many human cancers (Wolfer et al, 2010). More recently, induction of FOXP3 by p53 following DNA damage in breast epithelial cells has been reported, with increased FOXP3 levels contributing to the growth-suppressive activity of the p53 pathway (Jung et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

et al. 2011

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The transcription factor FOXP3 has been identified as a tumour suppressor in the breast and prostate epithelia, but little is known about its specific mechanism of action. We have identified a feed-forward regulatory loop in which FOXP3 suppresses the expression of the oncogene SATB1.In particular, we demonstrate that SATB1 is not only a direct target of FOXP3 repression, but that FOXP3 also induces two miRs, miR-7 and miR-155, which specifically target the 3 0 -UTR of SATB1 to further regulate its expression. We conclude that FOXP3-regulated miRs form part of the mechanism by which FOXP3 prevents the transformation of the healthy breast epithelium to a cancerous phenotype. Approaches aimed at restoring FOXP3 function and the miRs it regulates could help provide new approaches to target breast cancer.

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

Cited by 153 publications

References 43 publications

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Biological reprogramming in acquired resistance to endocrine therapy of breast cancer

Asymmetric cancer cell division regulated by AKT

FOXP3 and FOXP3-regulated microRNAs suppress SATB1 in breast cancer cells

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