Oncotarget

Research Papers:

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

Nathalie Zatula, Maria Wiese, Jens Bunzendahl, Walter Birchmeier, Christina Perske, Annalen Bleckmann and Felix H. Brembeck _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:6770-6787. https://doi.org/10.18632/oncotarget.2252

Metrics: PDF 2599 views  |   HTML 3383 views  |   ?  


Abstract

Nathalie Zatula1,4, Maria Wiese1,4, Jens Bunzendahl1,4, Walter Birchmeier2, Christina Perske3, Annalen Bleckmann4 and Felix H. Brembeck1,4

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2252