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The BCL9-2 proto-oncogene governs estrogen receptor alpha expression in breast tumorigenesis

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Item Type:Article
Title:The BCL9-2 proto-oncogene governs estrogen receptor alpha expression in breast tumorigenesis
Creators Name:Zatula, N. and Wiese, M. and Bunzendahl, J. and Birchmeier, W. and Perske, C. and Bleckmann, A. and Brembeck, F.H.
Abstract:The majority of human breast cancers express estrogen receptor {Alpha} (ER), which is important for therapy with anti-estrogens. Here we describe the role of BCL9-2, a proto-oncogene previously characterized as co-activator of Wnt/{beta}-catenin signaling, for mammary tumorigenesis in mice and human. ER positive human breast cancers showed overexpression of BCL9-2 and tamoxifen treated patients with high BCL9-2 demonstrated a better survival. BCL9-2 was upregulated during puberty and pregnancy in normal mammary epithelia, but downregulated in the involuted gland. BCL9-2 overexpression in vivo delayed the mammary involution and induced alveolar hyperplasia. Moreover, aged BCL9-2 transgenic mice developed ductal-like mammary tumors with high nuclear ER expression. We found, that primary cell cultures of BCL9-2 breast tumors responded to tamoxifen treatment. Moreover, BCL9-2 regulated the expression of ER and the proliferation of human breast cancer cells independently of {beta}-catenin. Finally, we describe a novel mechanism, how BCL9-2 regulates ER transcription by interaction with Sp1 through the proximal ESR1 gene promoter. In summary, BCL9-2 induces ER positive breast cancers in vivo, regulates ER expression by a novel {beta}-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.
Keywords:Mouse Model, Primary Cell Culture, Human Breast Cancer, Canonical Wnt Signaling, Estrogen Receptor Pathway, Pygo2, Sp1, Animals, Mice
Source:Oncotarget
ISSN:1949-2553
Publisher:Impact Journals (U.S.A.)
Volume:5
Number:16
Page Range:6770-6787
Date:30 August 2014
Official Publication:http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2252&path[]=3720
PubMed:View item in PubMed

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