The biology of tumor progression in different breast cancer subtypes
Breast cancer starts in the epithelial cells lining the mammary gland ducts. In the earliest stages, tumor cells grow intraductally as ductal carcinoma in situ (DCIS). At some point, the basement membrane may degrade, and tumor cells invade surrounding tissue and form invasive tumors. There exist no reliable biomarkers for identifying which DCIS patients will progress to have invasive disease, thus all patients are treated as if they have potentially invasive tumors. This leads to substantial overtreatment. The aim of this project is to study the role of established molecular subtypes in breast tumor progression with special emphasis on the HER2 and FGFR1 signaling pathways. We will use intraductal and orthotopic (fat-pad) xenografts to model tumor progression in vivo. Using injection of syngeneic cell lines, we will specifically explore the role of the immune system in tumor progression.
Mice will receive human or mouse cancer cells using the mouse intraductal injection method (MIND) or the more conventional orthotopic implantation method in the mammary gland fat-pad. Parts of the experiments in this project include administration of HER2/FGFR1 inhibitors. It is expected that mice will undergo moderate short-term distress in treatment periods and during surgery, but the single animal burden is in total low. Since we study early progression of breast tumors, most mice will be euthanized at an early stage, before appearance of any significant clinical symptoms caused by the tumor. All mice will be closely monitored using tumor measure and weight logs. Mice will be humanely euthanized if they reach predefined humane endpoints.
Results from this project will contribute with increased understanding of tumor progression of early breast cancer lesions. Understanding the role of FGFR1 and HER2 signaling in breast tumor progression may lead to more precise patient stratification and more optimal treatment of patients with DCIS. Importantly, this project aims to contribute to reduce overtreatment.
In this project we plan to use a maximum of 1000 mice. In the experiments that include human cell lines we will use NXG immunodeficient mice, while for the syngeneic experiments, we will use either FVB/N, C57BL/6 or BALB/c, matching the genetic background of the cell lines.
These animal experiments are parts of a larger project on breast tumor progression including analyses of genomic data from human cohorts and in vitro cell-line experiments. In vitro pilot experiments have already been performed to select cell lines relevant for in vivo experiments to reduce the number of animals needed. To ensure adequate effect, HER2/FGFR1 inhibitors will be tested on the relevant cell lines in vitro before treating animals. We have tested in vitro invasion assays to investigate whether this method could replace modeling invasion in vivo, but there was little concurrence between in vitro and in vivo invasion, therefore, in vivo experiments are needed. Our group already has experience in using the MIND method, and we have learned that this approach is considerably less invasive than other methods of tumor implantation. All surgical procedures will be performed by a trained operator using appropriate anesthesia and analgesia.
Mice will receive human or mouse cancer cells using the mouse intraductal injection method (MIND) or the more conventional orthotopic implantation method in the mammary gland fat-pad. Parts of the experiments in this project include administration of HER2/FGFR1 inhibitors. It is expected that mice will undergo moderate short-term distress in treatment periods and during surgery, but the single animal burden is in total low. Since we study early progression of breast tumors, most mice will be euthanized at an early stage, before appearance of any significant clinical symptoms caused by the tumor. All mice will be closely monitored using tumor measure and weight logs. Mice will be humanely euthanized if they reach predefined humane endpoints.
Results from this project will contribute with increased understanding of tumor progression of early breast cancer lesions. Understanding the role of FGFR1 and HER2 signaling in breast tumor progression may lead to more precise patient stratification and more optimal treatment of patients with DCIS. Importantly, this project aims to contribute to reduce overtreatment.
In this project we plan to use a maximum of 1000 mice. In the experiments that include human cell lines we will use NXG immunodeficient mice, while for the syngeneic experiments, we will use either FVB/N, C57BL/6 or BALB/c, matching the genetic background of the cell lines.
These animal experiments are parts of a larger project on breast tumor progression including analyses of genomic data from human cohorts and in vitro cell-line experiments. In vitro pilot experiments have already been performed to select cell lines relevant for in vivo experiments to reduce the number of animals needed. To ensure adequate effect, HER2/FGFR1 inhibitors will be tested on the relevant cell lines in vitro before treating animals. We have tested in vitro invasion assays to investigate whether this method could replace modeling invasion in vivo, but there was little concurrence between in vitro and in vivo invasion, therefore, in vivo experiments are needed. Our group already has experience in using the MIND method, and we have learned that this approach is considerably less invasive than other methods of tumor implantation. All surgical procedures will be performed by a trained operator using appropriate anesthesia and analgesia.