YB-1 Mediates a Crosstalk between ERα and TGFβ Signaling in Breast Cancer Cells.

The multifunctional Y-box binding protein-1 (YB-1) belongs to the highly conserved family of cold shock proteins being involved in transcriptional/translational regulation, DNA repair as well as stress response. Additionally, it is highly expressed in many malignant tissues which seems to correlate with a high proliferation level, drug resistance and a poor prognosis in a variety of tumors including breast cancer.Using quantitative immunohistochemistry we now confirm the previously described negative prognostic impact of YB-1 on survival in a clinical study with tumor samples from 199 breast cancer patients (p=0.0146; median follow up 79 months).Treatment of the estrogen receptor α (ERα) positive human breast cancer cell line MCF-7 with antiestrogens (4-hydroxytamoxifen, faslodex) resulted in a time and dose dependent decrease of YB-1 expression on the RNA- as well as on the protein level. In contrast, antiestrogen treatment of the ERα negative cell line MDA-MB-231 does not have any effect indicating that the antiestrogen effect on YB-1 is mediated by ERα. We have already demonstrated that the action of all antiestrogens is at least partially mediated by transforming growth factor β (TGFβ) (e.g. Breast Cancer Res. Treat. 107: 15-24, 2008). Using TGFβ-responsive reporter gene assays we now show that overexpression of YB-1 in MCF-7 cells enhances the induction of p3TPlux activity by TGFβ suggesting a crosstalk between YB-1 and TGFβ signaling pathways. Moreover, YB-1 also increases the antiestrogen induction of the TGFβ2-mRNA level coming along with a YB-1 regulated enhancement of the antiestrogen effect on cell growth.Very recent findings of our group point towards a ligand-independent influence of ERα on TGFβ signaling (Breast Cancer Res. Treat., in press). Due to the antiestrogen regulation of YB-1 via ERα and its crosstalk with the TGFβ pathway, the potential role of YB-1 as a mediator of the interaction between ERα and TGFβ signaling was analyzed. Performing pull-down assays with recombinant GST-ERα and whole cell lysates of MCF-7 cells confirms a protein-protein interaction between YB-1 and ERα. The physiological relevance of this interaction could be demonstrated, as the TGFβ-induced p3TPlux activity is clearly modulated by both, YB-1 and ERα.In conclusion, we present evidence that YB-1 and TGFβ signaling are functionally linked in MCF-7 cells. Combined with the detection of a physical interaction between YB-1 and ERα, our findings shed new light on a potential role of YB-1 as a part of the mechanism responsible for switching TGFβ from its anti-proliferative role in early tumor stages to tumor promoting effects in late-stage disease, most likely via a YB-1 regulated shift of TGFβ-signaling to pro-invasive pathways. This would also explain why high levels of YB-1 correlate with a poor prognosis in breast cancer patients.

Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 4172.