Fibroblast role in the acquisition and maintenance of breast cancer resistance to anti-HER2 therapies. Identification of novel compensatory tyrosine kinase receptors
HER2 positivity defines a molecular subtype of breast cancer with an aggressive biological behaviour and poor prognosis. Its pharmacological targeting with the monoclonal antibody Trastuzumab, and later on with the small tyrosine kinase inhibitor Lapatinib, changed the prognosis for HER2-positive br...
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| Tipo de recurso: | tesis doctoral |
| Estado: | Versión publicada |
| Fecha de publicación: | 2016 |
| País: | España |
| Institución: | CBUC, CESCA |
| Repositorio: | TDR. Tesis Doctorales en Red |
| OAI Identifier: | oai:www.tdx.cat:10803/396186 |
| Acceso en línea: | http://hdl.handle.net/10803/396186 |
| Access Level: | acceso abierto |
| Palabra clave: | Càncer de mama Cáncer de mama Breast cancer Fenotip Fenotipo Phenotype Anticossos monoclonals Anticuerpos monoclonales Monoclonal antibodies Ciències de la Salut 616 |
| Sumario: | HER2 positivity defines a molecular subtype of breast cancer with an aggressive biological behaviour and poor prognosis. Its pharmacological targeting with the monoclonal antibody Trastuzumab, and later on with the small tyrosine kinase inhibitor Lapatinib, changed the prognosis for HER2-positive breast cancer patients. However, despite the positive results from many trials, resistance to anti-HER2 agents occurs in both metastatic and adjuvant settings, in part, because HER2 represent just a part of a more complex biological network, that when deregulated, plays a central role in sustaining the aggressive phenotype of tumour cells. Moreover, the importance of the tumour microenvironment in drug resistance has been recognized during the last years, and it is now widely accepted that growth, survival and metastasis (as a consequence of treatment failure), are regulated by stromal-cancer cell interactions. Then, it is likely that the tumour stroma, and cancer associated fibroblasts in particular, influence also the therapeutic outcome. Therefore, our hypothesis is that during the acquisition of drug resistance cancer and stromal cells co-evolve, and that the tumour cells can induce changes in the structure and composition of the microenvironment to support their own growth and progression or dissemination. Our research has defined a coevolution process between breast cancer cells and fibroblasts where fibroblasts and BC cells crosstalk drives the drug resistant phenotype. We have identified RET and FGFR2 pathways as novel mechanisms of HER2 activation and we have demonstrated the importance of the interaction between these pathways in vitro and in vivo, in promoting breast cancer progression and resistance to Trastuzumab and Lapatinib. Furthermore, we propose that inhibition of RET and FGFR2 pathways might become a promising strategy after Trastuzumab and Lapatinib failure in patients with HER2-positive breast cancer. |
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