Understanding tumor invasion and metastasis provides crucial information with respect to carcinoma progression. Towards this goal, we have identified a mesodermal gene, Twist, which has a crucial role in promoting breast cancer formation. Earlier results from this laboratory have indicated that over-expression of Twist, a basic helix-loop-helix transcription factor, in MCF-7 breast cancer cells promotes tumorigenesis and increased vasculature and permeability within the tumor microenvironment of xenografts. Preliminary data have indicated that over-expression of this transcription factor can promote the expression of the choline kinase, a marker related to malignant transformation and metastasis. In addition, the activity of the increased levels of choline kinase is evident from the elevated levels of phosphocholine and total choline containing compounds in these transgenic cells. The present proposal is designed to understand the role of Twist in promoting breast cancer invasion and metastasis by altering the cellular physiology and biochemistry of breast epithelium by using functional imaging techniques. The three specific aims are: 1) To identify biochemical and physiological alterations in orthotopic tumors using Twist over-expressing breast cancer cells by functional magnetic resonance imaging and spectroscopy, 2) To functionally characterize and image the effects of down- regulating Twist in breast cancer xenograft models, and 3) To identify novel metastatic markers in Twist over-expressing cells and to validate them in breast cancer patient samples. In this study, we will use functional magnetic resonance imaging to identify the molecular changes that influence the phenotypic characteristics of breast tumors, such as, changes in choline containing compound levels, lactate levels, extracellular pHe, vascular volume and permeability surface area product in Twist over-expressing as well in Twist down-regulated cells. Also, we will use non-invasive optical imaging to identify various stages of cancer progression using MCF-7/Twist cells transfected with an optical reporter gene (tdTomato). Finally, the gene signature patterns identified using the preclinical model will be applied to patient samples in order to identify potential markers of breast cancer progression. In the long term, these studies will help in the pathological diagnosis of breast cancer and provide insights that will contribute to the development of novel imaging markers and chemotherapeutic drugs for breast cancer.

Public Health Relevance

Metastatic disease is the principle cause of death from breast cancer. Molecular characterization of this process is crucial to the development of novel diagnostic and therapeutic agents that will alleviate patient suffering and increase the survival rate. In this research proposal, we will use functional magnetic resonance imaging to identify the molecular changes that influence the phenotypic characteristics of breast tumors, such as, changes in choline containing compound levels, lactate levels, extracellular pHe, vascular volume and permeability surface area product in Twist over-expressing breast cancer cells. Finally, the gene signature patterns of metastatic progression identified using Twist over-expressing breast cancer cells in preclinical model will be applied to patient samples in order to identify potential markers of breast cancer progression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA140226-05
Application #
8597523
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Jhappan, Chamelli
Project Start
2010-03-10
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$297,082
Indirect Cost
$115,934
Name
Johns Hopkins University
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218