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    Research Grants Awarded

    Imaging Metastatic Potentials Of Breast Cancer

    Grant Mechanism:
    Career Catalyst Research

    Scientific Abstract:
    Background and Rationale: Breast cancer is usually treated with surgery followed by adjuvant therapy in clinic. Physicians decide the aggressiveness of adjuvant therapy based on how likely the breast tumor will relapse evaluated by factors such as tumor stage and grade, etc. More aggressive adjuvant therapy is adopted for tumors of higher grade and later stage. However, current system of tumor classification of stage and grade does not accurately predict the metastatic potential of a tumor, i.e., how likely the cancer will have distant relapse. For example, low-grade breast tumors treated less aggressively may disseminate while high-grade tumors treated aggressively may be indolent in nature. If breast cancer recurrence occurs with metastasis, the prognosis is very poor since effective methods for treating systemic disease are not yet available. The adjuvant therapy strategy may be substantially modified if a physician knows how likely metastasis will occur. However, the metastatic prognosis is mostly uncertain for breast cancer. To predict the metastatic potential of human breast cancers, we propose to employ two clinically transferable methods, a noninvasive magnetic resonance imaging (MRI) method and a low temperature optical imaging method that could be performed on biopsy specimens on studying breast cancer mouse xenografts. The MRI method measures T1rho, the magnetic resonance relaxation time of water proton in rotating frame in tissue. The low temperature fluorescence imaging of reduced pyridine di-nucleotides (NADH) and flavoprotein (Fp) reflects the mitochondrial redox status and oxidative metabolism. Our preliminary data on mouse xenografts of five human melanoma cell lines have shown that the aggressive tumors with higher metastatic potentials exhibit higher T1rho relaxation rates (1/T1rho) and higher mitochondrial redox ratios than the indolent tumors. The correlation of these biomarkers with the invasive potentials of these cell lines is high (R2 > 0.9), suggesting that this set of imaging techniques may provide novel and reliable imaging markers for the clinical prediction of metastatic potentials of solid tumors. We propose to translate our findings that T1?-MRI and mitochondrial redox status correlates with metastatic behavior, to breast cancer progression. We will apply these novel imaging techniques to predict metastatic behavior using a panel of well characterized and established breast cancer lines that span the range of cancer progression to metastasis. Objective/Hypothesis: The goal of this proposal is to identify in mouse xenografts reliable imaging biomarkers of human breast cancer for predicting their metastatic potentials. The general hypothesis is that an optimal imaging marker can be based on T1rho-MRI and NADH/Fp fluorescence imaging (or combinations of parameters derived by the two methods), which will correlate well with the metastatic potentials (in vitro invasive potentials and/or in vivo metastatic rates) of human breast cancers. Specific Aims: 1) to measure the aggressiveness in terms of the invasive potentials in vitro and the metastatic rates (metastases burden) in vivo for a panel of breast cancer cell lines (MDA-MB-231, MDA-MB-436, Hs578T, BT-474, MCF-7 - all engineered to express firefly luciferase); 2) to evaluate T1rho as a surrogate marker of aggressiveness for breast cancer xenografts; 3) to evaluate mitochondrial redox status as a marker of aggressiveness for breast cancer xenografts. Optimum imaging markers of breast cancer metastatic potentials may be obtained by integrating T1rho and mitochondrial redox status. Study Design: The invasive abilities of the proposed five human breast cell lines will be confirmed in vitro using a membrane invasion culture system. The luciferase expressing breast cancer cells will then be inoculated orthotopically into the mammary fat pads of athymic nude mice. The metastatic rates of the grown tumors will be evaluated by weekly bioluminescence imaging of metastases in vivo and colony counts in bones, lungs, livers, and brain by necropsy. The human breast cancer xenografts will also be subjected to MRI study. Tumors will then be excised from the snap-frozen mice for low temperature NADH/Fp fluorescence imaging and confirmation of the MRI results. Imaging biomarkers such as T1rho and redox ratios will be correlated with the invasive abilities in vitro and/or metastatic rates in vivo of these cancer cell lines to identify imaging biomarker(s) of breast cancer metastatic potentials. Benefit of Research: This project is aimed to uncover imaging biomarkers of breast cancer metastatic potentials that may lead to clinical applications. Knowledge of the metastatic potential of tumors at the time of surgery would help physicians to determine the aggressiveness of the surgical procedures and adjuvant therapy as well as the frequency of post-surgical surveillance. Thus, severe side effects caused by over-treatment or relapses due to under-treatment can be reduced, resulting in significantly higher survival rate and improved quality of life of patients. In addition, this study may contribute to the current knowledge of breast cancer progression and metastasis.

    Lay Abstract:
    Primary breast cancer is commonly treated with surgery followed by chemo-therapy in the clinic. Physicians decide the aggressiveness of adjuvant therapy based on how likely the tumor will relapse evaluated by factors such as tumor stage and grade. Physicians will select more aggressive adjuvant therapy for tumors of higher grade and later stage than tumors of earlier stage and lower grade. However, the current system of tumor classification of stage and grade does not accurately predict the metastatic potential of a tumor, i.e., how likely the cancer will have distant relapse. For example, low-grade breast tumors treated less aggressively may disseminate while high-grade tumors treated aggressively may be indolent in nature. In this project we propose to develop a new grading system for breast cancer using quantitative imaging biomarkers that we have shown to be highly correlated with tumor metastatic potential in animal models. We employ a magnetic resonance imaging (MRI) method and a low temperature optical imaging method. The non-invasive MRI technique is sensitive to cellular microenvironment and it is readily transferable to clinic. The optical imaging method identifies the metabolic status of cancer cells. It can be performed on biopsy specimens to provide tumor aggressiveness biomarkers previously unknown. With these two methods, we have successfully graded the aggressiveness of five human melanomas grown in mice that vary widely in rates of metastasis. We will extend these imaging techniques to study a panel of human breast tumors grown in mice. The metastatic potentials of these breast tumors will be assessed by the invasive ability of cancer cells in cell culture and the amount of distant metastases in the body. The parameters obtained by the proposed MRI and optical imaging of these tumors will be correlated with the amount of distant metastases and the invasive ability in cell culture to identify biomarkers of metastatic potentials. These novel imaging biomarkers if successfully developed, offer several advantages over the traditional methods. First, they provide information directly related to cellular biological processes and metabolism inside the body. Although the underlying mechanism of metastatic potential is complex and not yet fully understood, biological processes on cellular levels are expected to reflect metastatic potential better than stage and grade. Secondly, they are continuously quantitative markers compared to the qualitative and discrete nature of tumor stage and grade. They are potentially capable of differentiating a full range of metastatic potentials within small increments, rather than just aggressive versus indolent or malignant versus benign. Thirdly, the higher resolution in space for MRI (100~200 æm) and optical imaging (50 æm) methods will provide fine details of the diverse nature inside the tumor. The diverse nature of tumor has been implicated in theoretical models for studying tumor metastatic potential. Although PET is a valuable tool in clinic and translational research, its resolution in space is currently limited to about 4-5 millimeter for patients. Since the spreading or metastasis of cancer to other parts of the body is the primary factor contributing to deaths related to cancer, this project identifying biomarkers of metastatic potential has high clinical significance. We expect these new clinically translatable imaging biomarkers, with further clinical validation, will provide key supplemental information for diagnosis and help physicians to better guide breast cancer therapies added to surgery. The tumors with higher metastatic potential may be treated more aggressively with scarce medical resources concentrated on those with greater risk of lethal metastases. Tumors with lower metastatic potential will be treated less aggressively. Thus, severe side effects caused by over-treatment can be reduced, resulting in higher survival rate and improved quality of life of patients. The biomarkers of tumor metastatic potential will also help guide doctors in the follow-ups of breast cancer survivors. In addition, the successful completion of this project will help researchers to understand more about breast tumor progression and metastasis, and help them to design better methods to predict and/or reduce the metastatic potentials of breast tumors to achieve a better clinical outcome for breast cancer patients.