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

// Nathalie Zatula 1,4 , Maria Wiese 1,4 , Jens Bunzendahl 1,4 , Walter Birchmeier 2 , Christina Perske 3 , Annalen Bleckmann 4 and Felix H. Brembeck 1,4 1 Tumor Biology and Signal Transduction, Georg-August-University Göttingen, Germany 2 Max-Delbrueck-Center for Molecular Medicine, Berlin, Germany 3 Dept. of Pathology, Georg-August-University Göttingen, Germany 4 Dept. of Hematology and Medical Oncology, Georg-August-University Göttingen, Germany Correspondence: Felix H. Brembeck, email: // Keywords : mouse model; primary cell culture; human breast cancer; canonical Wnt signaling; estrogen receptor pathway; Pygo2; Sp1 Received : April 04, 2014 Accepted : July 24, 2014 Published : July 25, 2014 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.