ErbB2 Receptor in Breast Cancer: Implications in Cancer Cell Migration, Invasion and Resistance to Targeted Therapy

Overexpression of ErbB2 is found in several types of human carcinomas. In breast tumors, ErbB2 overexpression is detected in up to 20% of patients. Breast cancers in with amplification of ErbB2 are characterized by rapid tumor growth, lower survival rate and increased disease progression. The molecular mechanisms underlying the oncogenic action of ErbB2 involve a complex signaling network that tightly regulates malignant cell migration and invasion and hence metastatic potential. Recent efforts have been made to identify gene expression signatures of ErbB2-positive invasive breast cancers that may represent important mediators of ErbB2-induced tumorigenesis and metastatic progression. In this chapter, we will discuss the canonical ErbB2 signaling pathways responsible for tumor growth and dissemination along with newly identified mediators such as adaptor protein p130Cas and miRNAs. From a therapeutic point of view, the treatment with anti-ErbB2 monoclonal antibody trastuzumab has greatly improved the outcomes of patients with ErbB2 aggressive cancer. Nevertheless, de novo and acquired resistance to trastuzumab therapy still represent a major clinical problem. In the second part of the chapter, we will provide an overview of the mechanisms so far implicated in the onset of resistance to targeted therapy and of the new strategies to overcome resistance

p130Cas promotes invasiveness of three dimensional ErbB2-transformed mammary acinar structures by enhanced activation of mTOR/p70S6K and Rac1

ErbB2 over-expression is detected in approximately 25% of invasive breast cancers and is strongly associated with poor patient survival. We have previously demonstrated that p130Cas adaptor is a crucial mediator of ErbB2 transformation. Here, we analysed the molecular mechanisms through which p130Cas controls ErbB2-dependent invasion in three-dimensional cultures of mammary epithelial cells. Concomitant p130Cas over-expression and ErbB2 activation enhance PI3K/Akt and Erk1/2 MAPK signalling pathways and promote invasion of mammary acini. By using pharmacological inhibitors, we demonstrate that both signalling cascades are required for the invasive behaviour of p130Cas over-expressing and ErbB2 activated acini. Erk1/2 MAPK and PI3K/Akt signalling triggers invasion through distinct downstream effectors involving mTOR/p70S6K and Rac1 activation, respectively. Moreover, in silico analyses indicate that p130Cas expression in ErbB2 positive human breast cancers significantly correlates with higher risk to develop distant metastasis, thus underlying the value of the p130Cas/ErbB2 synergism in regulating breast cancer invasion. In conclusion, high levels of p130Cas favour progression of ErbB2-transformed cells towards an invasive phenotype

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness

Dysregulation of Blimp1 transcriptional repressor unleashes p130Cas/ErbB2 breast cancer invasion

ErbB2 overexpression is detected in approximately 20% of breast cancers and is correlated with poor survival. It was previously shown that the adaptor protein p130Cas/BCAR1 is a crucial mediator of ErbB2 transformation and that its overexpression confers invasive properties to ErbB2-positive human mammary epithelial cells. We herein prove, for the first time, that the transcriptional repressor Blimp1 is a novel mediator of p130Cas/ErbB2-mediated invasiveness. Indeed, high Blimp1 expression levels are detected in invasive p130Cas/ErbB2 cells and correlate with metastatic status in human breast cancer patients. The present study, by using 2D and 3D breast cancer models, shows that the increased Blimp1 expression depends on both MAPK activation and miR-23b downmodulation. Moreover, we demonstrate that Blimp1 triggers cell invasion and metastasis formation via its effects on focal adhesion and survival signaling. These findings unravel the previously unidentified role that transcriptional repressor Blimp1 plays in the control of breast cancer invasiveness

Identification of p130Cas/ErbB2-dependent invasive signatures in transformed mammary epithelial cells

Understanding transcriptional changes during cancer progression is of crucial importance to develop new and more efficacious diagnostic and therapeutic approaches. It is well known that ErbB2 is overexpressed in about 25% of human invasive breast cancers. We have previously demonstrated that p130Cas overexpression synergizes with ErbB2 in mammary cell transformation and promotes ErbB2-dependent invasion in three-dimensional (3D) cultures of human mammary epithelial cells. Here, by comparing coding and non-coding gene expression profiles, we define the invasive signatures associated with concomitant p130Cas overexpression and ErbB2 activation in 3D cultures of mammary epithelial cells. Specifically, we have found that genes involved in amino acids synthesis (CBS, PHGDH), cell motility, migration (ITPKA, PRDM1), and angiogenesis (HEY1) are upregulated, while genes involved in inflammatory response (SAA1, S100A7) are downregulated. In parallel, we have shown that the expression of specific miRNAs is altered. Among these, miR-200b, miR-222, miR-221, miR-R210, and miR-424 are upregulated, while miR-27a, miR-27b, and miR-23b are downregulated. Overall, this study presents, for the first time, the gene expression changes underlying the invasive behavior following p130Cas overexpression in an ErbB2 transformed mammary cell model

Colorectal Hyperplasia and Dysplasia Due to Human Carcinoembryonic Antigen (CEA) Family Member Expression in Transgenic Mice

CEA and CEACAM6 are immunoglobulin family intercellular adhesion molecules that are up-regulated without structural mutations in approximately 70% of human cancers. Results in in vitro systems showing tumorigenic effects for these molecules suggest that this correlation could indicate an instrumental role in tumorigenesis. To test whether this applies in vivo, transgenic mice harboring 187 kb of the human genome containing four CEA family member genes including the CEA and CEACAM6 genes were created and their copy numbers increased by mating until colonocyte expression levels reached levels seen in human colorectal carcinomas. The colonocyte surface level of integrin α5 and the activation of AKT increased progressively with the expression levels of CEA/CEACAM6. Colonic crypts showed a progressive increase in colonocyte proliferation, an increase in crypt fission, and a strong inhibition of both differentiation and anoikis/apoptosis. All transgenic mice showed massively enlarged colons comprising a continuous mosaic of severe hyperplasia, dysplasia and serrated adenomatous morphology. These results suggest that up-regulated non-mutated adhesion molecules could have a significant instrumental role in human cancer

The Caldera. No. 24

El poder extraordinario que tiene la literatura, en la vida de un ser humano, es incalculable; no sólo es abrir un libro y pasar los ojos por las páginas; ¡No! Es dejarse atrapar, dejarse llevar por mundos y contextos distintos, diversos, pletóricos de vivencias humanas que nos hacen únicos e irrepetibles. Cada vez que abrimos un libro y nos damos el permiso de leerlo, nos volvemos mejores seres humanos, porque comprendemos más al otro, o por lo menos, tratamos de reconocer cómo vivían, cómo pensaban, cómo actuaban, en otras épocas, incluyendo la nuestra. Con la lectura, podemos entender por qué los seres humanos son como son, potenciamos la empatía y fortalecemos la conciencia moral, entre algunas ventajas que tiene este proceso que nos acompaña a lo largo de toda la vida. Este año, en la mejor Feria del Libro del Oriente Colombiano, ULIBRO 2021, que se realiza del 30 de agosto, al 4 de septiembre, estamos invitados a participar en conversatorios, talleres, encuentros con autores, entre otras actividades propuestas, de manera presencial y virtual, para seguir fortaleciendo nuestro proyecto de vida; también, estamos invitados a dejarnos contagiar de la lectura, de la escritura, de la oralidad, a partir de “Las historias asombrosas”, que se van a tomar los diferentes espacios propuestos.1. Experiencias Internacionales…5 2. Homenaje al Dr. Alfonso Gómez Gómez; Por Samir Rodríguez Sarmiento…12 3. Nuestro Preescolar; Por Pilar Rocío Silva, Clara María Hassen y Laura Melissa Ayala…16 4. Maestros Caldistas; Por Gisela Afanador Díaz y Elena Mireya Brijaldo…20 5. Reloj Solar…24 6. La Cuna de Excélsior. VIII Concurso de Lectura en Voz Alta…29 7. VIII Concurso Intercolegiado Departamental de Oratoria...35 8. Homenaje a Augusto Monterroso; Por comunidad caldista...49 9. Expresiones Caldistas…52 10. Galería de Imágenes…86 11. Nuestros Maestros…92The extraordinary power that literature has, in the life of a human being, is incalculable; It is not just opening a book and running your eyes through the pages; No! It is to let yourself be trapped, to let yourself be carried away by different, diverse worlds and contexts, full of human experiences that make us unique and unrepeatable. Every time we open a book and give ourselves permission to read it, we become better human beings, because we understand others more, or at least, we try to recognize how they lived, how they thought, how they acted, in other times, including ours. . With reading, we can understand why human beings are the way they are, we enhance empathy and strengthen moral conscience, among some advantages that this process has that accompanies us throughout our lives. This year, in the best Book Fair of the Colombian East, ULIBRO 2021, which takes place from August 30 to September 4, we are invited to participate in talks, workshops, meetings with authors, among other proposed activities, in person and virtual, to continue strengthening our life project; Also, we are invited to let ourselves be infected with reading, writing, orality, starting from "The amazing stories", which are going to take the different spaces proposed