B49
Bidirectional receptor crosstalk in breast cancer: implications for future treatment strategies
Dearbhaile Collins1, Sinead Cocchiglia1, Arnold Hill2, Leonie Young1
1Royal College of Surgeons in Ireland, Dublin, Ireland, 2Beaumont Hospital, Dublin, Ireland
Background
Progression of breast cancer despite hormonal and biological treatments continues to pose a therapeutic challenge. Receptor crosstalk can occur between the estrogen receptor (ER) and the receptor tyrosine kinases, such as HER2, when ER-positive tumours are inhibited by Tamoxifen and anastrozole. We hypothesized that treatment with tyrosine kinase receptor inhibitors (TKI), trastuzumab (Herceptin) and lapatinib (Tyverb), could induce similar receptor crosstalk by inhibiting growth factor pathways and overactivating endocrine-driven tumour growth.
Method
Proteomic analysis (LC-Mass Spectrometry) was used to assess proteins that interact with the proto-oncogene, c-Myc, that is involved in tumourigenesis and invasion. We compared proteins in the endocrine-sensitive MCF7 cells and endocrine-insensitive LCC1 cells. Coimmunoprecipitation, immunoblotting, luciferase assays, siRNA experiments and MTS assays were utilized to investigate our findings.
Results
Liquid Chromatography Mass Spectrometry revealed a novel interaction between the proto-oncogene c-Myc and the corepressor, SMRT/NCoR2 in endocrine sensitive breast adenocarcinoma MCF7 cell line, but not in the ER and HER2 positive LCC1 cell line. SMRT is silencing the oncogenic effects of c-Myc in the less invasive tumour model. Coimmunoprecipitation revealed this interaction was lost when cells were treated with TKIs only, thus liberating c-Myc from SMRT repression. When anti-estrogen treatments were also utilised, SMRT/c-Myc interaction was re-established. siRNA and luciferase assays confirmed this interaction as functionally important in breast cancer proliferation and progression. In our HER2-overexpressing breast cancer patient population who received trastuzumab, those who also overexpressed ER were noted to have an increased risk of recurrence (36% vs 18%, p<0.0001).
Conclusion
This bidirectional receptor cross-talk phenomenon has clear implications for the future treatment of breast cancer, identifying tumours that are more likely to progress despite TKI therapy and patients who would benefit from both anti-estrogen and anti-growth factor therapies.
