Gene expression signature of estrogen receptor α status in breast cancer

Abba, Martı́n C.; Hu, Yuhui; Sun, Hongxia; Drake, Jeffrey; Gaddis, Sally; Baggerly, Keith A.; Şahin, Ayşegül; Aldaz, C. Marcelo

doi:10.1186/1471-2164-6-37

Cited by 132 publications

(103 citation statements)

References 41 publications

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“…Patients with tumors that express ER␣ have a longer disease-free interval and overall survival than patients with tumors that lack ER␣ expression; this indicates that ER␣ may be a key regulator of breast cancer susceptibility (25). However, the molecular basis for the association between ER␣ expression, hormonal responsiveness, and breast cancer prognosis remains unclear (26), and the other genes involved in breast cancer susceptibility need to be found. ER␤ is another estrogen receptor in sporadic breast tumors.…”

Section: Discussionmentioning

confidence: 99%

Estrogen Receptor (ER) β or p53 Attenuates ERα-mediated Transcriptional Activation on the BRCA2 Promoter

Jin

Chen

et al. 2008

Journal of Biological Chemistry

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BRCA2 is closely related to the pathogenesis of breast cancer. In the present study, we found that estrogen can activate BRCA2 transcription, which is estrogen receptor (ER) ␣-dependent. During estrogen treatment, ER␣ interacted with CREB-binding protein/p300, p68/p72, and MyoD and formed an activating transcriptional complex that could bind to many Sp1 sites on the BRCA2 promoter and activate its transcription by inducing histone acetylations. MyoD is a new component of ER␣ complex. ER␤ or p53 attenuated ER␣-mediated transcriptional activation by preventing the recruitment of ER␣ transcriptional complex and histone acetylations on the BRCA2 promoter. ER␤ interacted with ER␣ and CREB-binding protein/p300 and formed a weak activating transcriptional complex that competed for binding to Sp1 sites with ER␣ transcriptional complex and slightly attenuated BRCA2 transcription. Different from ER␤, p53 interacted with HDAC1 and CtBP1 and formed an inhibiting transcriptional complex that could compete for binding to Sp1 sites with ER␣ transcriptional complex and inhibit BRCA2 transcription more significantly.Breast cancer is the second leading cause of death in American women, accounting for more than 50,000 deaths each year. The breast cancer and ovarian susceptibility genes 1 and 2 (BRCA1 and BRCA2) 3 were identified based on their genetic linkage to familial early onset of breast and ovarian cancer syndromes (1-3). Mutations in the BRCA1 and BRCA2 are characterized by predisposition to familial breast and ovarian cancer. However, reduced levels of wild-type BRCA1 and BRCA2 expression have been detected in a large percentage of sporadic breast tumors in the absence of BRCA1 and BRCA2 mutations (4 -6), suggesting that defects in transcriptional regulation of the BRCA1 and BRCA2 genes contribute to sporadic breast and ovarian tumorigenesis (7,8). Detection of this transcriptional regulation in cancer cells may provide a molecular mechanistic basis for sporadic breast and ovarian tumor formation.In addition to attenuation of BRCA1 and BRCA2 expression by mutation or promoter hypermethylation, BRCA1 and BRCA2 expression are also controlled by transcriptional factors (9). There are only a few studies about the promoter transcription of BRCA2. Nuclear factor-B can activate the BRCA2 promoter activity (10); p53 represses the BRCA2 promoter activity and down-regulates BRCA2 mRNA and protein levels in response to DNA damage (11). So far, there is no report on how estrogen receptor (ER) ␣ activates BRCA2 transcription during E 2 treatment and how ER␤ or p53 attenuate the BRCA2 transcription by competing with ER␣ transcriptional complex for binding to Sp1 sites on the BRCA2 promoter region upstream of the transcription start site. In this study, we investigated changes in these complexes on the BRCA2 promoter region and their effects on BRCA2 transcription. EXPERIMENTAL PROCEDURESCell Lines, Culture, Plasmids, and Transfection-Human breast cancer cell lines MDA-MB-231 and MCF-7 were maintained in RPMI 1640 medium containing 10% f...

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Section: Discussionmentioning

confidence: 99%

Estrogen Receptor (ER) β or p53 Attenuates ERα-mediated Transcriptional Activation on the BRCA2 Promoter

Jin

Chen

et al. 2008

Journal of Biological Chemistry

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“…The number of genes regulated by E2 in MCF7 cells, ranges from 100 to 1500. These largely appear to be involved in signaling pathways controlling cell proliferation, invasion and metastasis (Kininis and Kraus, 2008;Abba et al, 2005). The finding that E2 also exhibits similar gene regulation in native human tumors further validates MCF7 cells as an estrogen signaling model system relevant to breast cancers (Creighton et al, 2006).…”

Section: Introductionmentioning

confidence: 90%

Monitoring proliferative activities of hormone-like odorants in human breast cancer cells by gene transcription profiling and electrical impedance spectroscopy

Pick

Terrettaz

Baud

et al. 2013

Biosensors and Bioelectronics

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a b s t r a c tThe human estrogen receptor alpha (ERα) mediates the proliferative action of hormones in breast cancer cells by regulating the expression of target genes to control cellular functions. Current methodologies do not permit a real-time assessment of these processes in living cells. We overcome this limitation using electrical cell-substrate impedance sensing for measuring ERα-regulated signaling processes indicative of the onset of cell proliferation to target them for compound screenings. We report that hormone like odorants regulate, similarly as natural estrogen, ERα-mediated gene expression involved in mitogenic and developmental processes in MCF7 breast cancer cells. An odorant concentration-dependent switch in cell responses was detectable already 10-15 h post-stimulation, providing rapid quantification of hormonal activity before cell division occurred. Though ERα exhibits complex regulatory roles our noninvasive approach captures its activity for accelerated screenings of compounds promoting breast cancer cell proliferation expanding the analysis of ERα signaling networks.

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“…These studies reveal that there are large-scale transcriptomic differences between ER+ and ER− breast cancers. For example, cell growth-related genes are predominately upregulated in ER+ cancer comparing to ER− cancer [13], whereas cell cycle related genes show predominantly higher expression in ER− cancer in comparison with ER+ cancer [14]. However, direct comparing the two subtypes cannot determine whether the DE genes result from dysregulated gene expression in ER+ cancers or ER− cancers in comparison to normal controls.…”

Section: Introductionmentioning

confidence: 99%

Genes Dysregulated to Different Extent or Oppositely in Estrogen Receptor-Positive and Estrogen Receptor-Negative Breast Cancers

Zhou

Shi

et al. 2013

PLoS ONE

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BackgroundDirectly comparing gene expression profiles of estrogen receptor-positive (ER+) and estrogen receptor-negative (ER−) breast cancers cannot determine whether differentially expressed genes between these two subtypes result from dysregulated expression in ER+ cancer or ER− cancer versus normal controls, and thus would miss critical information for elucidating the transcriptomic difference between the two subtypes.Principal FindingsUsing microarray datasets from TCGA, we classified the genes dysregulated in both ER+ and ER− cancers versus normal controls into two classes: (i) genes dysregulated in the same direction but to a different extent, and (ii) genes dysregulated to opposite directions, and then validated the two classes in RNA-sequencing datasets of independent cohorts. We showed that the genes dysregulated to a larger extent in ER+ cancers than in ER− cancers enriched in glycerophospholipid and polysaccharide metabolic processes, while the genes dysregulated to a larger extent in ER− cancers than in ER+ cancers enriched in cell proliferation. Phosphorylase kinase and enzymes of glycosylphosphatidylinositol (GPI) anchor biosynthesis were upregulated to a larger extent in ER+ cancers than in ER− cancers, whereas glycogen synthase and phospholipase A2 were downregulated to a larger extent in ER+ cancers than in ER− cancers. We also found that the genes oppositely dysregulated in the two subtypes significantly enriched with known cancer genes and tended to closely collaborate with the cancer genes. Furthermore, we showed the possibility that these oppositely dysregulated genes could contribute to carcinogenesis of ER+ and ER− cancers through rewiring different subpathways.ConclusionsGPI-anchor biosynthesis and glycogenolysis were elevated and hydrolysis of phospholipids was depleted to a larger extent in ER+ cancers than in ER− cancers. Our findings indicate that the genes oppositely dysregulated in the two subtypes are potential cancer genes which could contribute to carcinogenesis of both ER+ and ER− cancers through rewiring different subpathways.

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Gene expression signature of estrogen receptor α status in breast cancer

Cited by 132 publications

References 41 publications

Estrogen Receptor (ER) β or p53 Attenuates ERα-mediated Transcriptional Activation on the BRCA2 Promoter

Estrogen Receptor (ER) β or p53 Attenuates ERα-mediated Transcriptional Activation on the BRCA2 Promoter

Monitoring proliferative activities of hormone-like odorants in human breast cancer cells by gene transcription profiling and electrical impedance spectroscopy

Genes Dysregulated to Different Extent or Oppositely in Estrogen Receptor-Positive and Estrogen Receptor-Negative Breast Cancers

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