Group Information

Breast cancer is one of the most common and heterogeneous cancers, in which ductal carcinomas represent 80% of all tumours. Based on different molecular profiles, ductal carcinomas are classified according to their worst prognosis as tumours that are positive for luminal A and luminal B oestrogens, HER2-positive or basal (ER-, PR-, HER2-negative). In addition to the oncogenes that support ductal breast carcinomas (PI3K, Ras, p53 mutations), alteration of relevant signalling nodules can crucially regulate cell networks related to cancer progression, strengthening key tumour features, such as aberrant proliferation, angiogenesis or invasion and metastasis.

Some of these molecular nodes incorporate multiple input signals and generate several output signals through the modulation of post-translational modifications, including phosphorylation, ubiquitination or acetylation of numerous regulatory and effector proteins. These nodes work as molecular switches that cooperate with oncogenic signalling pathways or act as compensatory signalling in normal pathways to trigger transformation or address vulnerabilities arising from the tumour.

Our studies indicate that serine/threonine kinase GRK2 is emerging as a relevant modulator of oncogenic signalling modules due to its ability to affect the ubiquitination and acetylation of a wide variety of proteins into transformed cells. GRK2 stimulates the activity of E3 Mdm2 ligase and HDAC6 deacetylase, which are key factors in transformation mediated by inhibition of tumour suppressors (p53) and modulation of molecules involved in cell cycle control, angiogenesis, stress responses or metastatic progression. In fact, the concurrent positive regulation of GRK2, Mdm2 and HDAC6 emerges as a functional module characteristic of luminal breast cancer cells that contributes to cell proliferation and survival. GRK2 also attenuates the functionality of ATM kinase, a central sensor of DNA damage and metabolic stress, which is also involved in the regulation of Mdm2 and p53. Additionally, our data show that the negative regulation of endothelial GRK2 is a relevant fact in the angiogenic change triggered by tumour cells, favouring a permissive microenvironment for tumour growth and metastasis.

Our main goals are to define the functional interrelation of Mdm2/p53/ATM/HDAC6 in transformed epithelial cells and endothelial cell response, to characterise the regulation of this signalling module by GRK2 under different stress conditions caused by the tumour environment and its consequences on breast cancer progression. Different integrated responses that contribute to tumour malignancy, such as invasiveness or cell senescence, will be analysed.

We are addressing how regulation of Mdm2/ATM/HDAC6 by GRK2 affects the metabolic and mitochondrial homeostasis of breast cells when genome integrity is compromised by nutrient overload, genotoxic agents or oxidative stress. We are also characterising the angiogenic response promoted by this signalling module and the molecular mechanisms involved in the concurrent and opposite changes of GRK2 in the epithelial (positive regulation) and vascular endothelial (negative regulation) components of breast tumours, responsible for intratumoral vascular remodelling.