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(Concepcion) Mechanisms of breast cancer and prostate cancer progression to recurrency and hormone resistance representing the lethal phenotype of the disease
Universidad de Concepcion
Department of Medical Specialties, Molecular Endocrinology and Oncology Lab
Mario Fuentealba, MD
Sergio Onate, PhD
English and Spanish
Type of Research Project
- Basic science
What is the background of the project?
Breast cancer (BrCa) and prostate cancer (CaP) clearly ara diseases that significantly impact a substantial number of women and men, causing severe morbidity and loss of life. Because these cancers are diseases with initial estrogen and androgen sensitivity that relapses as hormone-resistant, there is no effective therapies for the treatment of the refractory disease. Understanding the molecular mechanism of the switch from hormone dependence to hormone resistance is an area of intense research and much effort has been devoted to the biology and the mechanisms of androgen and estrogen action in cancer epithelial cells that cause changes in ligand sensitivity, in the context of the tumor cell microenvironment. The results in our lab demonstrate that altered interactions between androgen and estrogen receptors and their co-regulators of transcription mediated by RNA pol II in tumor cells have the potential to contribute to tumor progression, in the context of bone stroma cells microenvironment. Our new and more advanced understanding of the mechanisms of stromal-epithelial cell interactions and the ramifications of these interactions represents an important and innovative area of research in BrCa and CaP progression and metastasis.
What is the aim of the project?
The aim of the project is to determine the mechanism of altered androgen regulation of genes in androgen-dependent and castration-resistant CaP, with a major emphasis on the changes of ER/AR coregulators during disease progression, in the context of bone cells microenvironment. The studies of the molecular mechanism(s) by which ER/AR function changes during CaP progression, from hormone-responsive to castration-resistant, will provide new therapies for the treatment of these devastating diseases.
What techniques and methods are used?
Hormone-responsive and hormone-independent tumor cells The androgen- sensitive cell lines LNCaP, and its androgen-resistant C4-2 pair, are well characterized and represent an alternative model of progression from prostate cancer to hormone resistance. Similarly, several breast cancer tumor cell lines isolated from different tumors, either hormone responssive or ligend independent are currently available for in vitro assays. These models are used in in vitro studies and in tissue recombination tumors and graft transplants (xenografts) models in mice with severe combined immunodeficiency syndrome (SCID). Experimentally, tumors representing hormone- dependent and hormone-independent tumors, are grown to a final volume of 1 cm 3 in approximately four weeks as tissue xenografts in SCID mice. At this time samples from each tumor are processed into fragments of 2-5 mm under sterile conditions and processed to: 1) freeze in liquid nitrogen for preservation at -150 oC and to preserve in RNAlater (Ambion, Austin, TX) for Extraction of RNA, genetic material, and proteins; 2) fix in 4% para-formaldehyde buffer solution for histology and immunohistochemistry studies. This tumors samples are available from the bioterium supervised by our collaborator, Dr. JR Toledo. Numerous cell lines and primary cultures derived from clinical samples are commercially available from the American Type of Cell Culture Collection (ATCC). Adenoviral expression system of reporter genes The use of adenovirus has the advantage that the cells in replication and in G 0 present in cell cultures and in primary cultures can be infected with high efficiency and the expression product analyzed in 24 hours. Our studies show that viral infection in cells in culture approaches 100% with minimal levels of cytotoxicity. Adenoviruses that use the Luciferase reporter gene under the control of different DNA sequences that are promoters and specific for androgens and estrogens (i) Ad-PSA- Luc; (ii) Ad-MMTV- Luc; (iii) Ad-FGF10- promoter-Luc, and have the ability to rapidly and effectively quantify the cellular response to androgens and different ligands. Therefore, we can determine the effect of different drugs on the ER/AR function in the absence and in combination with other antagonist ligands in the same cell. Reporter genes encoding green fluorescent protein (GFP) or red (RFP) allow the capture of images of infected cells for monitoring in vitro and in vivo and are commercially available. Therefore, cloning of different reporters will provide efficient and specific sensitivity to different ligands. Clinical samples of breast and prostate cancer Pilot studies that requires the use of tumor cancer cells isolated from clinical samples is limited and are preserved in liquid nitrogen in the tumor bank of our collaborator Dr. J. Madariaga and C. Delgado, Department of Pathology and Tumor Banking Research Department, Regional Hospital (HGGB ) and the School of Medicine, University of Concepcion. Tissue samples are routinely analyzed by the central histology/pathology lab and classified as benign or malignant tissue. Cells are obtained by digestion of the tissue with collagenase and cultured in the presence of 10% fetal bovine serum. Epithelial cells are fractionated after digestion. Cellular fractionation and phenotype characterization is performed using activated fluorescence fractionation and associated flow cytometry (FACS) available in our laboratory, in collaboration with Dr. A. Chandia.
What is the role of the student?
- The student will observe the practical experiments but will be highly involved in the analysis of the results
What are the tasks expected to be accomplished by the student?
To prepare a poster and a presentation containing a scientific report. Upon the results obtained, the student’s name will be mentioned in a future publication. If the results are as expected, the student will have the opportunity to present together with the supervisor the results on a conference. However, as this is a short research rotation, no specific outcome can be expected in advance.
Will there be any theoretical teaching provided (preliminary readings, lectures, courses, seminars etc)
What is expected from the student at the end of the research exchange? What will be the general outcome of the student?
- The student will prepare a poster - The student will prepare a presentation - The student’s name will be mentioned in a future publication - The student will have the opportunity to present the results together with the supervisor at a conference
What skills are required of the student? Is there any special knowledge or a certain level of studies needed?
X Subjects passed: Basic transcription and gene expression X Previous experience with: lab techniques at the undergraduate level
Are there any legal limitations in the student’s involvement
Type of students accepted
This project accepts: - Medical students - Pre-Medical students from the American-British system - Students in biomedical fields
- search for mechanisms of transcription regulation and coregulators at NCBI; PubMed central; McNerney EM and Onate SA; Nuclear Receptor Research; 2016; Villagran et al; Biophysical and Biochemical Research Communication; 2015.
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