A Mechanistic Investigation of Insulin Receptor Substrate 2 Function in Breast Cancer Progression

The advancement of cancer treatment depends on understanding the biological processes that contribute to disease progression. The spread of tumor cells from the primary site to distant organs is the biggest obstacle to efficacious treatment. The insulin receptor substrate (IRS) proteins IRS1 and IRS2 are cytoplasmic adaptor proteins that organize signaling events downstream of the Insulin receptor (IR) and the Insulin-like growth factor receptor 1 (IGF1R). Both of these receptors have been implicated in cancer progression. The IRS proteins share a significant level of homology and are both capable of recruiting and activating phosphatidylinositol-3 kinase (PI3K). Despite these similarities, signaling through IRS1 and IRS2 leads to distinct tumor cell outcomes in vitro and in vivo. In vitro, IRS1 regulates cell proliferation and growth and IRS2 regulates metabolism, survival and invasion. In vivo, Irs2 is a positive regulator of tumor metastasis, whereas Irs1 does not promote metastasis. The major objective of this thesis work was to further the understanding of the mechanism by which IRS2 signaling regulates tumor progression. To investigate how IRS-1 and IRS-2 regulate distinct tumor cell outcomes, I examined the involvement of the microtubule cytoskeleton in IRS-dependent signaling. I determined that IRS2-mediated AKT activation is dependent upon an intact microtubule cytoskeleton, whereas IRS1-mediated AKT signaling occurs independently of microtubules. As a result, drugs that disrupt microtubules promote apoptosis in cells that signal through IRS2, but cells that signal through IRS1 are resistant to the effects of microtubule disruption. However, AKT inhibition sensitizes IRS1-dependent cells to apoptotic cell death upon microtubule disruption. From a clinical perspective, my studies identify IRS2 as a potential biomarker for the response of breast cancer patients to anti-microtubule drug therapy. To investigate further the mechanism of IRS2 contributions to tumor progression, I employed a mutagenesis approach to identify structural requirements of IRS2 for its function. I established that the ability of IRS2 to activate PI3K is necessary for its regulation of both invasion and tumor initiating cell (TIC) self-renewal. I also identified two independent regions within the IRS2 C-terminus that are required for invasion and self-renewal, respectively. Characterization of the invasion-promoting region identified BMP2-induced protein kinase (BMP2K) as an interacting protein. Suppression of BMP2K expression in mammary tumor cells disrupts IRS2-mediated tumor cell invasion. Taken together, my work advances the understanding of how IRS2 contributes to breast cancer progression and provides a molecular understanding for the development of novel approaches for the treatment of breast cancer and other malignancies that rely upon IRS2

RUNX1 and breast cancer

News on: Runx1 stabilizes the mammary epithelial cell phenotype and prevents epithelial to mesenchymal transition, by Hong et al. Oncotarget. 2017; 8:17610-27. doi: 10.18632/oncotarget.15381

ESTIMADOS DE ÍNDICE DE ÁREA FOLIAR Y RAZÓN DE ASIMILACIÓN NETA PARA APIO

ESTIMADOS DE ÍNDICE DE ÁREA FOLIAR Y RAZÓN DE ASIMILACIÓN NETA PARA API

Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2

Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion, and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor (IR) activation and the recruitment and activation of phosphatidylinositol 3-kinase (PI3K), functions shared with IRS1. In addition, a 174-amino-acid region in the IRS2 C-terminal tail, which is not conserved in IRS1, is also required for IRS2-mediated invasion. Importantly, this invasion (INV) region is sufficient to confer invasion-promoting ability when swapped into IRS1. However, the INV region is not required for the IRS2-dependent regulation of glucose uptake. Bone morphogenetic protein 2-inducible kinase (BMP2K) binds to the INV region and contributes to IRS2-dependent invasion. Taken together, our data advance the mechanistic understanding of how IRS2 regulates invasion and reveal that IRS2 functions important for cancer can be independently targeted without interfering with the metabolic activities of this adaptor protein

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2- but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment

Nivelatorios: Estrategia para mitigar deserción académica precoz

En Colombia, toda Institución de Educación Superior [IES], conoce el estado académico con el cual ingresan los estudiantes a primer semestre gracias al examen de Estado SABER 11 el cual “…es requisito para ingresar a los programas de pregrado…” (Ley 1324 del Congreso de la Republica de Colombia. (2009). Este examen es diseñado y administrado por el Instituto Colombiano para la Evaluación de la Educación98[ICFES] y a partir de los resultados de este examen, se pueden definir estrategias de acompañamiento para evitar la deserción académica precoz. Acorde con lo anterior, la Universidad Simón Bolívar ha establecido unos lineamientos para el fortalecer las competencias de lectura y matemáticas de los estudiantes quienes ingresan en primer semestre. Dentro de estos lineamientos están los cursos nivelatorios que han sido implementados para que los estudiantes puedan recibir refuerzos en dichas competencias antes del inicio las actividades académicas reglamentarias y poder superar con mayor facilidad las dificultades académicas con las cuales ingresan. Estos refuerzos se siguen realizando durante todo el primer semestre. El requisito para que los estudiantes participen en estos cursos es haber obtenido un puntaje igual o inferior a 60 puntos en las pruebas de lectura crítica y matemáticas. En el proceso de nivelatorios se manejan 3 etapas: 1. Curso intensivo de 20 horas antes de iniciar el calendario académico programado, 2. Curso básico: refuerzos semanales desde el Departamento de Ciencias Sociales y Humanas y el área de Ciencias exactas. 3. Medición de impacto con respecto a rendimiento académico en cursos afines asignados en primer semestre. Con el ejercicio realizado desde el periodo académico 2018-1 se ha logrado obtener una muestra de los estudiantes con puntajes por debajo o igual a 60 quienes realizaron los cursos nivelatorios, frente a quienes no lo hicieron y se ha podido evidenciar un impacto positivo en el rendimiento académico de los estudiantes en los cursos afines. Es importante recalcar que la estrategia aún no es obligatoria para los estudiantes, sin embargo, se ofrece como una de las alternativas de acompañamiento académico desde primer a último semestre con la finalidad de aumentar el índice de permanencia académica con calidad en la Universidad

Insulin Receptor Substrate-1 (IRS-1) and IRS-2 expression levels are associated with prognosis in non-small cell lung cancer (NSCLC)

The insulin-like growth factor-1 (IGF-1) signaling pathway has been implicated in non-small cell lung cancer (NSCLC) outcomes and resistance to targeted therapies. However, little is known regarding the molecular mechanisms by which this pathway contributes to the biology of NSCLC. The insulin receptor substrate (IRS) proteins are cytoplasmic adaptor proteins that signal downstream of the IGF-1R and determine the functional outcomes of this signaling pathway. In this study, we assessed the expression patterns of IRS-1 and IRS-2 in NSCLC to identify associations between IRS-1 and IRS-2 expression levels and survival outcomes in the two major histological subtypes of NSCLC, adenocarcinoma (ADC) and squamous cell carcinoma (SCC). High IRS-2 expression was significantly associated with decreased overall survival in adenocarcinoma (ADC) patients, whereas low IRS-1 cytoplasmic expression showed a trend toward association with decreased overall survival in squamous cell carcinoma (SCC) patients. Tumors with low IRS-1 and high IRS-2 expression were found to be associated with poor outcomes in ADC and SCC, indicating a potential role for IRS-2 in the aggressive behavior of NSCLC. Our results suggest distinct contributions of IRS-1 and IRS-2 to the biology of ADC and SCC that impact disease progression

The Insulin and IGF Signaling Pathway Sustains Breast Cancer Stem Cells by IRS2/PI3K-Mediated Regulation of MYC

Despite the strong association of the insulin/insulin-like growth factor (IGF) signaling (IIS) pathway with tumor initiation, recurrence, and metastasis, the mechanism by which this pathway regulates cancer progression is not well understood. Here, we report that IIS supports breast cancer stem cell (CSC) self-renewal in an IRS2-phosphatidylinositol 3-kinase (PI3K)-dependent manner that involves the activation and stabilization of MYC. IRS2-PI3K signaling enhances MYC expression through the inhibition of GSK3β activity and suppression of MYC phosphorylation on threonine 58, thus reducing proteasome-mediated degradation of MYC and sustaining active pS62-MYC function. A stable T58A-Myc mutant rescues CSC function in Irs2−/− cells, supporting the role of this MYC stabilization in IRS2-dependent CSC regulation. These findings establish a mechanistic connection between the IIS pathway and MYC and highlight a role for IRS2-dependent signaling in breast cancer progression