CONTROL EXTRAGONADAL DE LH: BASES MOLECULARES DE LA INVASIÓN Y METÁSTASIS EN CÁNCER DE MAMA

MONDACA JOSELINA MAGALI; FLAMINI MARINA INES; SANCHEZ ANGEL MATIAS

Becas de formación inicial en investigación en Cáncer 2013-2014. Informes finales quinta cohorte de becarios.

1a ed . - Ciudad Autónoma de Buenos Aires : Instituto Nacional del Cáncer, 2018.

Lugar: Buenos Aires; Año: 2018; p. 309 - 311

Breast cancer is the most common neoplasm in women. Globally, in our country 10-15% of women will be diagnosed with breast cancer throughout their lives, so it is necessary to develop new approaches for the prevention and treatment of breast cancer. Approximately 98% of cancer deaths are a consequence of metastasis. Cell migration, crucial for the development of invasion and metastasis, is a multi-step process involving the polarization and extension of membrane protrusions towards the direction of cell migration. These steps are conducted sequentially through a dynamic remodeling of the actinic cytoskeleton, continuing with the formation of focal adhesion complexes and finally the triggering of actinic nucleation/ branching, modulating in this way, the plasticity of the cell membrane by controlling key proteins of such processes. This is why our project pretend to determine the control mechanism regulated by gonadotropin called leutinizing hormone (LH), and how it could regulate key steps that trigger the motility of breast cancer cells through the recruitment of Focal adhesion kinase (FAK) (responsible for the formation of focal adhesion complexes). Once these processes are triggered, they are eventually promoted to actinic nucleation/branching regulated by proteins belonging to the Wiskott-Aldrich Syndrome Protein (WASP) family, such as N-WASP. N-WASP plays an important role in the formation of actinic scaffolds. This protein binds actinic filaments and promotes the polymerization/depolymerization process by means of its phosphorylated / dephosphorylated state, respectively. N-WASP transmits signals from specific GTPases (such as cdc42) to the Arp2/3 complexes, resulting in actinic polymerization or branching. This process seems to be essential in the rapid formation of actinic networks towards the periphery of the cell, providing the necessary protrusion force for the formation of specialized structures, promoting cell migration and invasion. This is why our work aims to: 1) Determine the effect of LH gonadotropins on the morphology regulation of breast cancer cells, through the study of key proteins in the formation of focal adhesion complexes (Src / FAK / Paxillin) and actinic nucleation (Cortactin/N-WASP/Arp2/3 and/or Cdc-42/N-WASP/Arp2/3) acting as potent regulators on cell movement. 2) To identify the molecular mechanisms by which LH would regulate / modulate, through specific phosphorylations, the activity of c-Src/FAK/Paxillin/Cortactin; Cortactin/N-WASP and Cdc-42/N-WASP, and the control mechanisms towards FAK/ Cortactin / N-WASP on the regulation of the Arp2/3 complex.