This is a second revision of a transdisciplinary proposal focusing on imaging and biology of early murine mammary cancers. We will employ quantitative serial magnetic resonance imaging with accompanying histology, immunohistochemistry, and X-ray fluorescence microscopy to understand the biology and natural history of in situ mammary cancer at initiation and progression. In addition, we will identify MRI parameters that detect various stages of mammary cancer, predict the future risk of progression to invasive cancer, and detect response to anti-angiogenic therapy. We will study C3(1)- SV40-Tag ('SVT') and MMTV-PyMT ('PMT') transgenic mice that develop MIN (mammary intraepithelial neoplasia;an intraductal neoplasia similar to DCIS in humans) and eventually invasive mammary cancers with a histological progression that is similar to poorly differentiated (basal type) and moderately differentiated breast cancers, respectively. Our collaboration was the first to demonstrate high resolution non-invasive imaging of in situ murine mammary cancer. Therefore, we are uniquely positioned to perform these highly integrated studies that take advantage of our unique strengths in small animal MRI imaging and cancer biology. We propose the following specific aims, taking advantage of our high field small animal MRI scanner, X-ray fluorescence microscopy at the Argonne National Labs, and extensive mammary gland biology research using animal models at the Ben-May Department of Cancer Research.
The Specific Aims of the research are: 1. Optimize functional and anatomic MRI of pre-cancerous and intraductal neoplastic changes. Develop accurate co-registration of MRI with histology, immunohistochemistry and X-ray fluorescence images. 2. Measure sensitivity and specificity of MRI for detection of early mammary cancers and pre-cancers using pathologic assessment as the gold standard. 3. Perform a serial imaging study of the natural history of mammary cancer in the SVT and PMT mice. Determine what percentage of early stage lesions detected by MRI progresses to the invasive stage. Identify MRI-detectable physiologic and anatomic markers that differentiate malignant from benign changes, and predict whether cancers will progress. At each time point some mice will be sacrificed so that MRI parameters can be correlated with histology, immunohistochemistry, and X-ray fluorescence images. 4. Use serial MRI to evaluate response of early cancers to B20 (a bevacizumab-type monoclonal antibody that binds mouse VEGF) in the SVT mice. At each time point studied by MR, several mice will be sacrificed so that MRI findings can be correlated with biomarkers. This research develops a new paradigm for the study of early breast cancer - a transdisciplinary approach involving imaging and tumor biology - allowing us to improve breast cancer detection and control.

Public Health Relevance

We propose to use high-resolution functional and anatomic magnetic resonance imaging of rodent mammary glands /in vivo/ to improve understanding of the natural history of pre-invasive human breast cancer and its precursors, to evaluate therapies that target early cancers, and to identify MRI markers for early cancers and cancer risk. This research will lead to improvements in the clinical management of high risk lesions and early breast cancer. We will study mouse mammary intra-epithelial neoplasia (MIN);this early, non-invasive neoplasia is very similar to ductal carcinoma in situ, or DCIS, in humans.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-OTC-W (02))
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Zhang, Huiming
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University of Chicago
Schools of Medicine
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He, Dianning; Zamora, Marta; Oto, Aytekin et al. (2017) Comparison of region-of-interest-averaged and pixel-averaged analysis of DCE-MRI data based on simulations and pre-clinical experiments. Phys Med Biol 62:N445-N459
Mustafi, Devkumar; Fernandez, Sully; Markiewicz, Erica et al. (2017) MRI reveals increased tumorigenesis following high fat feeding in a mouse model of triple-negative breast cancer. NMR Biomed 30:
Medved, Milica; Li, Hui; Abe, Hiroyuki et al. (2017) Fast bilateral breast coverage with high spectral and spatial resolution (HiSS) MRI at 3T. J Magn Reson Imaging 46:1341-1348
Markiewicz, Erica; Fan, Xiaobing; Mustafi, Devkumar et al. (2017) MRI ductography of contrast agent distribution and leakage in normal mouse mammary ducts and ducts with in situ cancer. Magn Reson Imaging 40:48-52
Andrews, Martin; Giger, Maryellen L; Roman, Brian B (2015) Manganese-enhanced MRI detection of impaired calcium regulation in a mouse model of cardiac hypertrophy. NMR Biomed 28:255-63
Mustafi, Devkumar; Zamora, Marta; Fan, Xiaobing et al. (2015) MRI accurately identifies early murine mammary cancers and reliably differentiates between in situ and invasive cancer: correlation of MRI with histology. NMR Biomed 28:1078-86
Mustafi, Devkumar; Gleber, Sophie-Charlotte; Ward, Jesse et al. (2015) IV Administered Gadodiamide Enters the Lumen of the Prostatic Glands: X-Ray Fluorescence Microscopy Examination of a Mouse Model. AJR Am J Roentgenol 205:W313-9
Chourasia, Aparajita H; Tracy, Kristin; Frankenberger, Casey et al. (2015) Mitophagy defects arising from BNip3 loss promote mammary tumor progression to metastasis. EMBO Rep 16:1145-63
Fan, Xiaobing; Macleod, Kay; Mustafi, Devkumar et al. (2015) Correlation of In Vivo and Ex Vivo ADC and T2 of In Situ and Invasive Murine Mammary Cancers. PLoS One 10:e0129212
Mustafi, Devkumar; Ward, Jesse; Dougherty, Urszula et al. (2015) X-ray fluorescence microscopy demonstrates preferential accumulation of a vanadium-based magnetic resonance imaging contrast agent in murine colonic tumors. Mol Imaging 14:

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