title: The BCL9-2 proto-oncogene governs estrogen receptor alpha expression in breast tumorigenesis.
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/ß-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 ß-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 ß-catenin independent mechanism in breast cancer cells, and might predict the therapy response to tamoxifen treatment.
authors.affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Zatula
authors.affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Wiese
authors.affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Bunzendahl
authors.affiliation: Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany.
authors.forename: Walter
authors.initials: W
authors.lastname: Birchmeier
authors.affiliation: Dept. of Pathology, Georg-August-University Göttingen, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Perske
authors.affiliation: Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
authors.forename: Annalen
authors.initials: A
authors.lastname: Bleckmann
authors.affiliation: Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany. Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany.
authors.forename: Felix H
authors.initials: FH
authors.lastname: Brembeck
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D063646:Carcinogenesis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000096:biosynthesis*; D005260:Female; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D000090063:Proto-Oncogene Mas; D013629:Tamoxifen / Q000494:pharmacology; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D015533:Transcriptional Activation; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495498:BCL9L protein, human; C568071:BCL9L protein, mouse; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D014157:Transcription Factors; D051176:beta Catenin; D013629:Tamoxifen