Estudio de la cooperación entre las rutas de HGF/MET y HH/PTCH en la transición epiteliomesénquima en tumores mamarios de ratón

Abstract

Breast cancer is a heterogeneous disease that involves and links a wide variety of cellsignaling pathways. HH/PTCH1 and HGF/MET pathways are engaged in embryonic development, morphogenesis and adult tissue homeostasis processes. Their regulation is altered in breast tumor development, in which they seem to play an important role in the process of epithelial-mesenchymal transition (EMT) which involves tumor initiating cells. These biochemical and morphological changes confer these cells the capacity of proliferation and migration from the primary tumor, thus generating metastasis. The aim of this work is to analyze a possible cooperation between both pathways by crosstalk in their downstream activation mechanisms that will lead to the epithelialmesenchymal transition (EMT) in breast tumors of transgenic mice over-expressing HH and HGF under the control or the whey acidic protein (WAP) promoter. To that end, their tumors were characterized for expression of cytokeratin markers of cell differentiation, as well as for expression of claudin 1 and E-cadherin, proteins involved in intercellular adhesion which frequently appear deregulated in processes of epithelial-mesenchymal transition. As a result, a crosstalk between both pathways has been identified that brings about a combined activation of the transcription factor snail1 resulting in repression of Ecadherin expression in bitransgenic mice. This cooperation between both pathways in the induction of the EMT program would support the decreased mammary epithelial cell differentiation and faster tumor growth in bitransgenic tumors previously observed by our group. In conclusion, the study of the cooperation between these pathways will be instrumental in the search of targets for more effective treatments against advanced stages of the disease, as a way to prevent processes leading to the tumor metastasis.