RESEARCH INTEREST
Breast cancer is a heterogeneous disease at both the molecular and histopathological levels, with diverse clinical outcomes, which complicates the development of targeted therapies. Its higher incidence in the developed world suggests that the Western lifestyle—characterized by unhealthy dietary patterns (excessive caloric intake, unbalanced diets, obesity) and chronic stress (adrenergic overstimulation)—may contribute to the onset and progression of the disease by progressively impairing genomic stability mechanisms. The histopathological diversity and molecular heterogeneity of breast tumours make it difficult to achieve effective treatments, and targeted drug therapies remain elusive for most aggressive forms of the disease. Another significant challenge is the emergence of resistance across all breast cancer subtypes. These limitations in current therapies highlight the urgent need for a deeper understanding of the complex pathways involved in breast cancer development and progression.
Our group seeks to identify regulatory nodes that integrate multiple cellular inputs and environmental cues to modulate tumor hallmarks such as genomic instability, cellular dissemination, and chemoresistance. Understanding how adaptable and dynamic signalling networks interact with breast cancer susceptibility genes will pave the way for better therapeutic approaches. We focus on interconnected alterations in the serine–threonine kinase GRK2 and associated ligases and deacetylases that function as oncomodulators in breast cancer, influencing both cell-autonomous transformation and interactions with the tumor microenvironment and the patient’s systemic state. Our results indicate that these proteins modulate each other differently in normal epithelial cells and in tumor cells, rewiring the signaling downstream G-protein coupled receptors (GPCR) or growth factor tyrosine kinase receptors (RTK).
We aim to understand how post-translational modifications controlled by the GRK2–Mdm2 ubiquitin axis and the HDAC6-dependent acetylome regulate a range of cellular processes including cell cycle control and cell division, differentiation, energy metabolism and senescence, which are key in maintaining a normal cell behavior. We also aim to gain insight into the connection of these molecules with hormonal (adrenergic, estrogenic) and metabolic stress, by analyzing its impact on proteins related to genomic stability (BRCA1 and others), as well as on stromal remodeling processes such as tumor angiogenesis, which together will promote tumor progression.
Estudio de las implicaciones funcionales de la serina-treonina quinasa de GRK2 en la telangectasia hemorrágica hereditaria. Fundación Ramón Areces. 2012-2015.
Interrelación de GRK2 con MDM2 y ATM en inestabilidad genómica por estrés metabólico y en la invasividad celular y angiogenesis: oportunidades terapéuticas en tumores de mama. PI14/00435. ISCIII. 2015-2017.
Esta ayuda está financiada por el Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 y el ISCIII – Subdirección General de Evaluación y Fomento de la Investigación – y cofinanciadas por el Fondo Europeo de Desarrollo Regional, Programa Operativo Crecimiento Inteligente 2014-2020 de acuerdo al Reglamento (UE) Nº 1303/2013.
Consecuencias del nodo MDM2/HDAC6/GRK2 en división celular, reparación de ADN y heterogeneidad del cáncer de mama: Potencial terapéutico del rebalanceo de quiescencia/senescencia. PI17/00576. ISCIII. 2018-2020.
Explorar la interrelación Mdm2/HDAC6/GRK2 en el modo de reparación del ADN en los patrones de división celular y en la geroconversión celular en tratamientos citotóxicos.
Esta ayuda está financiada por el Plan Estatal de Investigación Científica y Técnica y de Innovación 2013-2016 y el ISCIII – Subdirección General de Evaluación y Fomento de la Investigación – y cofinanciadas por el Fondo Europeo de Desarrollo Regional, Programa Operativo Crecimiento Inteligente 2014-2020 de acuerdo al Reglamento (UE) Nº 1303/2013.
Penela P, Nogués L, Mayor F. Role of G protein-coupled receptor kinases in cell migration. Curr. Opin. Cell Biol. 2014. 27: 10-17. FI: 8,467(Q1). PMID: 24680425. DOI: 10.1016/j.ceb.2013.10.005.
Fernández-Arenas E, Calleja E, Martínez-Martín N, Gharbi SI, Navajas R, García-Medel N, Penela P, Alcamí A, Mayor F, Albar JP, Alarcón B. beta-arrestin-1 mediates the TCR-triggered re-routing of distal receptors to the immunological synapse by a PKC-mediated mechanism. EMBO J 2014. 33: 559-577. FI: 10,434(Q1). PMID: 24502978. DOI: 10.1002/embj.201386022.
Rivas V, Carmona R, Muñoz-Chápuli R, Mendiola M, Nogués L, Reglero C, Miguel-Martín M, García-Escudero R, Dorn GW, Hardisson D, Mayor F, Penela P. Developmental and tumoral vascularization is regulated by G protein-coupled receptor kinase 2. J. Clin. Invest. 2013. 123: 4714-4730. FI: 13,765(Q1). PMID: 24135140. DOI: 10.1172/JCI67333.
Lafarga, Vanesa, Aymerich, Ivette, Tapia, Olga, Mayor, Jr., Federico, Penela, Petronila. A novel GRK2/HDAC6 interaction modulates cell spreading and motility. EMBO J 2012. 31: 856-869. FI: 9,822(Q1). PMID: 22193721. DOI: 10.1038/emboj.2011.466.
Penela P, Rivas V, Salcedo A, Mayor F. G protein-coupled receptor kinase 2 (GRK2) modulation and cell cycle progression. Proc Natl Acad Sci U S A 2010. 107: 1118-1123. FI: 9,771(Q1). PMID: 20080565. DOI: 10.1073/pnas.0905778107.
