Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

Newman, Simon P.; Bates, Nicholas P; Vernimmen, Douglas; Parker, Malcolm G.; Hurst, Helen C.

doi:10.1038/sj.onc.1203416

Cited by 89 publications

(61 citation statements)

References 38 publications

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“…Another possibility is that other regulatory elements, located outside the promoter region tested in this study, could influence ERBB2 expression in colon and ovary cancer cells. For instance, sequences described in the first intron (Newman et al, 2000) or 12 kb upstream the conventional start site of the ERBB2 gene (Nezu et al, 1999) should be studied. We also have to keep in mind the multiple levels of erbB-2 mRNA and protein expression regulation.…”

Section: Discussionmentioning

confidence: 99%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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The ERBB2 gene is overexpressed in 30% of breast cancers and this has been correlated with poor prognosis. ERBB2 is upregulated in other cancers such as prostate, pancreas, colon and ovary. In breast cancer cells, the mechanisms leading to ERBB2 gene overexpression are increased transcription and gene amplification. In these cancers, AP-2 transcription factors are involved in ERBB2 overexpression, and AP-2 levels are correlated with p185 c-erbB-2 levels. In this work, we wanted to know if the same molecular mechanisms are responsible for the ERBB2 upregulation in non-breast cancers. We compared ERBB2 gene copy number, p185 c-erbB-2 and mRNA levels with AP-2 levels in several ovary, prostate, colon and pancreas cancer cells. A moderate expression of erbB-2 mRNA and protein were observed in some cells without gene amplification. In contrast to breast cancer cells, AP-2 factors were absent or low in some non-breast cells which did express ERBB2. It is thus likely that AP-2 is not a major player in the increased levels of erbB-2 transcripts in non-breast cancer cells. The transcriptional activity of the ERBB2 promoter in colon and ovary cancer cells was estimated using reporter vectors. The results showed that the promoter regions involved in ERBB2 gene overexpression in breast cancer cells are different from those that lead to the gene upregulation in colon and ovary cancers. In conclusion, our results indicate that different transcriptional and post-transcriptional mechanisms are responsible for the increased levels of erbB-2 transcript and protein in breast and non-breast cancer cells.

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Section: Discussionmentioning

confidence: 99%

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Vernimmen¹,

Guéders²,

Pisvin

et al. 2003

Br J Cancer

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“…However, tamoxifen-bound ESR1 recruits NCOR allowing ERBB2 transcription to be activated (Newman et al 2000). Hence, long-term treatment with tamoxifen could potentially lead to increased ERBB2 expression influencing the cellular localization of the ESR1.…”

Section: S Pancholi Et Al: Erbb2 Influences Localization Of Esr1mentioning

confidence: 99%

ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2

Pancholi

Lykkesfeldt²,

Hilmi³

et al. 2008

Endocrine Related Cancer

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Acquired resistance to endocrine therapies remains a major clinical obstacle in hormone-sensitive breast tumors. We used an MCF-7 breast tumor cell line (Tam -1 cells could be partially overcome by the ERBB2 inhibitor AG825 in combination with tamoxifen, and this was associated with re-localization of ESR1 to the nucleus. These data demonstrate that tamoxifen-resistant cells have the ability to switch between ERBB2 or ESR1 pathways promoting cell growth and that pharmacological inhibition of ERBB2 may be a therapeutic strategy for overcoming tamoxifen resistance.

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“…Estrogen administration to breast cancer cell lines results in transcriptional repression of ErbB2. Independent studies found the ErbB2 promoter to be suppressed by either estrogen-induced downregulation or sequestration of the AP-2 or SRC-1 transcription factors respectively (Newman et al, 2000;Perissi et al, 2000).…”

Section: Estrogen Represses Erbb2 Expression and Vice Versamentioning

confidence: 99%

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

2000

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Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21 Waf1 plays an important role in evasion from apoptosis. These recent ®ndings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance. Oncogene (2000) 19, 6102 ± 6114.

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Cofactor competition between the ligand-bound oestrogen receptor and an intron 1 enhancer leads to oestrogen repression of ERBB2 expression in breast cancer

Cited by 89 publications

References 38 publications

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

Different mechanisms are implicated in ERBB2 gene overexpression in breast and in other cancers

ERBB2 influences the subcellular localization of the estrogen receptor in tamoxifen-resistant MCF-7 cells leading to the activation of AKT and RPS6KA2

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

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