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


  • N. Zatula
  • M. Wiese
  • J. Bunzendahl
  • W. Birchmeier
  • C. Perske
  • A. Bleckmann
  • F.H. Brembeck


  • Oncotarget


  • Oncotarget 5 (16): 6770-6787


  • 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.