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AP-2β activates enhancers that define mammary hormone sensing cell identity [RNA-seq]

ABSTRACT: The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE207472 | GEO | 2023/12/31

REPOSITORIES: GEO

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AP-2β activates enhancers that define mammary hormone sensing cell identity [ChIP-Seq]

Project description:The Activating Protein 2β transcription factor (TFAP2B; AP-2β) is a marker for both lobular and molecular apocrine/HER2-E breast cancers, despite these tumours having very different prognoses. We show that simultaneous expression of both AP-2β and the estrogen receptor (ESR1, ER) marks well differentiated, low proliferation cells that are characteristic of luminal A lobular tumours, but loss of ER expression occurs when the tumour cells progress to molecular apocrine tumours. To discover potential explanations for this behaviour we performed chromatin immunoprecipitation sequencing (ChIP-seq) for AP-2β, AR, GATA3, FOXA1 and H3K27 acetylation in ER-negative MDA-MB-453 breast cancer cells. We find that all four transcription factors frequently bind to the same enhancers and that these enhancers are more likely to be active when AP-2β is present. Molecular apocrine genes are significantly more likely to have enhancers bound to all four transcription factors flanked by H3K27 acetylation. When AP-2β binds separately from the other factors, it binds close to the transcription start site, where it shows very high enrichment for H3K27 acetylation. AP-2 family proteins activate transcription by recruiting CITED proteins and p300/CBP. Since AR, FOXA1 and GATA3 are themselves able to recruit histone acetyl-transferases, we infer that AP-2β regulates the activity of those histone acetyl-transferases. We propose that this broad fundamental role in transcription explains the contradictory functions, both oncogenic and tumour suppressing, that have been assigned to AP-2 family members in previous studies on cancer.

2023-12-31 | GSE207230 | GEO

ChIP-seq study using a cell line model of ER_ AR+ molecular apocrine tumours (AR_FoxA1_molecular_apocrine)

Project description:Breast cancer is a heterogeneous disease and several distinct subtypes exist based on differential gene expression patterns. Molecular apocrine tumours were recently identified as an additional subgroup, characterised as oestrogen receptor negative and androgen receptor positive (ER_ AR+), but with an expression profile resembling ER+ luminal breast cancer. One possible explanation for the apparent incongruity is that ER gene expression programmes could be recapitulated by AR. Using a cell line model of ER_ AR+ molecular apocrine tumours (termed MDA-MB-453 cells), we map global AR binding events and find a binding profile that is similar to ER binding in breast cancer cells. We find that AR binding is a near-perfect subset of FoxA1 binding regions, a level of concordance never previously seen with a nuclear receptor. AR functionality is dependent on FoxA1, since silencing of FoxA1 inhibits AR binding, expression of the majority of the molecular apocrine gene signature and growth cell growth. These findings show that AR binds and regulates ER cis-regulatory elements in molecular apocrine tumours, resulting in a transcriptional programme reminiscent of ER-mediated transcription in luminal breast cancers.

2012-02-18 | E-MTAB-986 | biostudies-arrayexpress

Gene expression data from AP-2γ silenced MCF-7 cells

Project description:Overexpression of the AP-2γ transcription factor in breast tumours has been identified as an independent predictor of poor outcome and failure of hormone therapy, even in ER positive, ErbB2 negative tumours; markers of a more favourable prognosis. To understand further the role of AP-2γ in breast carcinoma, we have used an RNA interference and gene expression profiling strategy using the MCF-7 cell line as a model for ER positive, ErbB2 negative tumours with AP-2γ overexpression. Gene expression changes between control and silenced cells implicate AP-2γ in the control of cell cycle progression and developmental signalling. Keywords: RNA interference

2009-12-14 | GSE15481 | GEO

Exploration of the redundancy between FOXA1 and AP2alpha in androgen receptor transcription complex

Project description:We performed a comparision of AR binding sites as well as the histone modifications H3K27 acetylation and H3K4 monomethylation in the presence and absence of FoxA1 in the molecular apocrine breast cancer cell line, MDA-MB-453. We also probed AP2alpha binding in asynchronous MDA-MB-453 cells.

2014-04-17 | E-MTAB-1694 | biostudies-arrayexpress

siRNA of human MCF-7 cells

Project description:Overexpression of the AP-2Î³ transcription factor in breast tumours has been identified as an independent predictor of poor outcome and failure of hormone therapy, even in ER positive, ErbB2 negative tumours; markers of a more favourable prognosis. To understand further the role of AP-2Î³ in breast carcinoma, we have used an RNA interference and gene expression profiling strategy using the MCF-7 cell line as a model for ER positive, ErbB2 negative tumours with AP-2Î³ overexpression. Gene expression changes between control and silenced cells implicate AP-2Î³ in the control of cell cycle progression and developmental signalling. Experiment Overall Design: We compared the expression profiles of MCF-7 cells separately transfected with three independent AP-2Î³ targeting sequences with those from control cells treated with transfection reagent alone or a non-silencing control siRNA on Affymetrix arrays; each condition was examined in triplicate.

2009-12-19 | E-GEOD-15481 | biostudies-arrayexpress

Genome-wide identification of AP-2α by ChIP-chip in breast cancer cell line MCF7

Project description:The AP-2 family of transcription factors is involved in the regulation of embryonic development, cell proliferation and tumorigenesis. To date, five members of the AP-2 family have been identified: AP-2α, AP-2β, AP-2γ, AP-2δ and AP-2ε. All AP-2 proteins bind as homo- or heterodimers to the consensus sequence of 5'- GCCNNNGGC-3' and directly regulate transcription of their target genes. Among these, AP-2α is the best-characterized gene.

2020-12-08 | GSE128589 | GEO

Mi-2β promotes immune evasion in melanoma by activating EZH2 methylation

Project description:Recent development of new immune checkpoint inhibitors has been particularly successfully in cancer treatment, but still the majority patients fail to benefit. Converting resistant tumors to immunotherapy sensitivity will provide a significant improvement in patient outcome. Here we identify Mi-2β as a key melanoma-intrinsic effector regulating the adaptive anti-tumor immune response. Genetically engineered mouse melanoma studies indicate that loss of Mi-2β rescued the immune response to immunotherapy in vivo. Mechanistically, ATAC-seq indicate that Mi-2β controlled the accessibility of IFN-γ-stimulated genes (ISGs). Mi-2β bound to EZH2 and promote K510 methylation of EZH2 and subsequently activate the trimethylation of H3K27 to inhibit the transcription of ISGs. Finally, we develop an Mi-2β-targeted inhibitor, Z36-MP5, which targeted inhibition of Mi-2β ATPase activity and recovered ISG transcription. Consequently, Z36-MP5 efficiently induce a response to immunotherapy in otherwise resistant melanomas. Our work provides a potential therapeutic strategy to convert immunotherapy resistant melanomas to sensitive ones.

2024-02-19 | GSE255782 | GEO

Breast Cancer Gene Expression Analysis

Project description:Analysis of 104 breast cancer biopsies (removed prior to any treatment with tamoxifen or chemotherapeutic agents) from patients aged between 31 years and 89 years at the time of diagnosis (mean age = 58 years). Twenty were less than 50 years and seventy-seven women were 50 years, or older, at diagnosis. The size of the tumours ranged between 0.6 cm and 8.0 cm (mean = 2.79 cm). Eighteen tumours were T1 (<2 cm) in maximal dimension; 83 were T2 (2M-bM-^@M-^S5 cm) and 3 tumours were T3 (>5 cm). Eighty-two were invasive ductal carcinoma, 17 were invasive lobular and five were tumours of special type (two tubular and three mucinous). Eleven tumours were grade 1; 40 were grade 2; and 53 were grade 3. Sixty-seven tumours were oestrogen receptor (ER) positive and 34 were ER negative (ER status was determined by Enzyme Immuno-Assay (EIA); a positive result was defined as more than 200 fmol/g protein). ER status was not available for 3 patients. Forty-five tumours had no axillary metastases and 59 tumours had metastasised to axillary lymph nodes. Sixty-nine women were treated with post-operative tamoxifen; 26 did not receive tamoxifen. Fifty patients were treated with adjuvant systemic chemotherapy (CMF +/M-bM-^HM-^R adriamycin); 45 patients did not receive chemotherapy. Details regarding tamoxifen and systemic chemotherapy were not available for 9 patients. Maximal follow-up was 3,026 days with a mean follow-up of 1,887 days. 17 normal breast tissues were also assayed. Gene expression profiling of 104 breast cancer and 17 normal breast biopsies.

2013-05-26 | E-GEOD-42568 | biostudies-arrayexpress

c-Jun/AP-1 overexpression reprograms ERα signaling related to tamoxifen response in ERα-positive breast cancer [expression profiling]

Project description:A critical mechanism that has been proposed for transcription regulation by estrogen receptor α (ER) is the tethering of ER to DNA via other transcription factors, such as AP-1. However, genome-wide assessment of the overlap in chromatin binding repertoires of these two transcription factors has not been reported. Here, we show that the AP-1 transcription factor c-Jun interacts with ER and that c-Jun chromatin binding shows extensive overlap with ER binding at the global level. Further, we show that c-Jun overexpression reprograms ER chromatin binding and modulates ER-mediated gene regulation. Our data are consistent with a mechanism where estrogen/ER-dependent crosstalk with AP-1 at the transcriptional level is mediated through the tethering of ER to DNA bound AP-1. Additionally, in our system c-Jun overexpression causes reduced sensitivity to tamoxifen in ER+ breast cancer cells. Integrated cistrome, transcriptome, and clinical data reveal TGFBI as a candidate gene which may confer tamoxifen resistance by ER and AP-1 crosstalk. Further, we show that TGFBI expression is elevated in breast cancer compared to normal breast. Together, our data provide a novel genome-wide footprint of ER and AP-1 crosstalk and suggest AP-1 and TGFBI signaling as potential therapeutic targets in AP-1-overexpressing ER-positive breast tumors.

2018-03-02 | GSE102367 | GEO

Transcription profiling of human invasive breast cancer carcinomas with different histological types and invasive lobular carcinoma

Project description:Gene expression array analysis on a series of ten different histological special types of invasive breast carcinomas (tubular, micropapillary, mucinous A, mucinous B, endocrine, apocrine, metaplastic, medullary, adenoid cystic, invasive ductal carcinoma with osteoclastic giant cells) and invasive lobular carcinoma.<br><br>Note: this experiment was reloaded into ArrayExpress in August 2010 to include mappings between raw and processed data files. It now includes additional dye-swap combined normalized data files.

2010-08-20 | E-NCMF-3 | biostudies-arrayexpress

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