Role of connexins during breast tumor development: study in tritransgenic mice and 3D primary cell culture

• Grant number: 14/19222-6
• Support Opportunities: Scholarships abroad - Research Internship - Post-doctor
• Start date: January 12, 2015
• End date: July 11, 2015
• Field of knowledge: Agronomical Sciences - Veterinary Medicine - Animal Pathology
• Principal Investigator: Maria Lucia Zaidan Dagli
• Grantee: Lucas Martins Chaible
• Supervisor: Martin Jechlinger
• Host Institution: Faculdade de Medicina Veterinária e Zootecnia (FMVZ). Universidade de São Paulo (USP). São Paulo , SP, Brazil
• Institution abroad: European Molecular Biology Laboratory, Monterotondo (EMBL), Italy
• Associated to the scholarship: 13/17108-9 - Effects of Increase of Cx43 gene expression in neoplasic lung cells transformed by tobacco carcinogen: In vitro and in vivo studies., BP.PD

Abstract

Metastatic breast cancer remains essentially incurable, highlighting the critical need for new therapeutic targets. Several experiments in vivo have investigated breast cancer progression towards metastasis. In certain cancers the trigger for cancer development are oncogenes expression or mutation that change the normal physiology of cells, and causing the cancer phenotype of a single cell that will generate the tumor. The connexins are membrane proteins that compose the gap junction communication, and several works described that they are down-regulated in a variety of carcinomas, suggesting that gap junctions play an important role in controlling cell differentiation, proliferation and preventing transformation. When connexins are overexpressed in neoplastic cells, tumor growth is slowed and the cells keep the original profile. In this project we propose study the connexin behavior in different stages of breast tumor development, and understand its role during the tumor progression in vio and in vitro. For this we propose two different steps: (1) To understand the connexin behavior we will perform in vivo and in vitro studies using the tritransgenic mouse (TetO-MYC;TetO-KrasG12D;MMTV-rtTA) and her primary mammary cells and analyze the connexins expression in the presence and absence of doxycycline to evaluate possible pattern changes. (2) Study the role persistence in connexin signal as well as loss of connexin signal at different stages of tumor induction and regression. For this we intend to study the interaction between normal and malignant breast cells using a co-culture of tritransgenic cells and normal cells, to create chimera acini. Our expectation is to find alterations in connexin expression during the tumor development, which we expect to be less pronounced in acini chimeras leading to a less aggressive tumor growth due to partial persistence of cell communication by the interspersion of non oncogene expressing cells. (AU)