[FPU2019] Role of Hippo pathway in hormone-dependent gene regulation and breast cancer proliferation

Estrogen and progesterone play critical roles in promoting the proliferation of both the normal and the neoplastic breast epithelium. Elucidating the molecular mechanisms governing hormone action is critical to understand not only breast cancer (BC) development but also human diseases caused by hormonal pathway dysregulation and malfunction, as observed in endocrine resistance. The 70% of BC tumours depend on estrogen for their growth and respond to treatment with anti-estrogen (e.g. tamoxifen) or aromatase inhibitors. However, approximately 30-50% percent of initially estrogen-dependent breast tumours become resistant to anti-estrogen treatment soon after the onset of therapy. Thus, identifying new target molecules for BC and developing combination therapies to address therapeutic resistance mechanisms need urgent attention and further elucidation.

Development of endocrine resistance in BC can be caused by pathways that provide alternative proliferation and survival stimuli to the tumours in the presence of effective inhibition of the estrogen receptor (ER) pathway. Previous findings point at the Hippo (YAP/TAZ) signaling as target candidate pathway, since its activation results in ER phosphorylation. Additionally, we have found that TEAD1, the transcription factor activated by Hippo signaling, binds to genomic regions occupied by ERa and progesterone receptor (PR). Moreover, our preliminary data indicate that inhibition of YAP/TAZ in the nucleus compromises hormone-dependent gene regulation as well as ERa and PR recruitment and BC cell proliferation.  YAP and TAZ hyperactivation might drive proliferation in tumours in which the functions of cell–cell adhesion proteins are compromised. However, its role in BC at molecular level is largely unknown  

The overall aim of this project is therefore to generate fundamental new knowledge on the function of the Hippo pathway for hormone-dependent breast cancer (BC) proliferation. We will therefore study, through global massive sequencing techniques as ChIP-seq, RNA-seq and ATAC-seq, mass spectrometry, and molecular cell biology approaches, the molecular mechanisms behind this crosstalk.
Specifically, in the proposed work programme, we will: (1) determine the biochemical mechanism by which YAP/TAZ crosstalks with ERa- and PR-dependent pathways genome wide, (2) evaluate if these pathways converge in liquid droplets in the cell nucleus to boost and provide an advantage for signal transduction, (3) identify new interactors involved in the crosstalk, and (4) use this knowledge for a screening of inhibitors in 3D organoids and patient derived xenografts (PDXs) that will indicate new therapeutic directions for BC management.