@article {323, title = {From Mouse to Human: Cellular Morphometric Subtype Learned From Mouse Mammary Tumors Provides Prognostic Value in Human Breast Cancer.}, journal = {Front Oncol}, volume = {11}, year = {2021}, month = {2021}, pages = {819565}, abstract = {

Mouse models of cancer provide a powerful tool for investigating all aspects of cancer biology. In this study, we used our recently developed machine learning approach to identify the cellular morphometric biomarkers (CMB) from digital images of hematoxylin and eosin (H\&E) micrographs of orthotopic -null mammary tumors (n = 154) and to discover the corresponding cellular morphometric subtypes (CMS). Of the two CMS identified, CMS-2 was significantly associated with shorter survival (p = 0.0084). We then evaluated the learned CMB and corresponding CMS model in transgenic mouse mammary tumors (n = 53) in which CMS-2 was significantly correlated with the presence of metastasis (p = 0.004). We next evaluated the mouse CMB and CMS model on The Cancer Genome Atlas breast cancer (TCGA-BRCA) cohort (n = 1017). Kaplan-Meier analysis showed significantly shorter overall survival (OS) of CMS-2 patients compared to CMS-1 patients (p = 0.024) and added significant prognostic value in multi-variable analysis of clinical and molecular factors, namely, age, pathological stage, and PAM50 molecular subtype. Thus, application of CMS to digital images of routine workflow H\&E preparations can provide unbiased biological stratification to inform patient care.

}, issn = {2234-943X}, doi = {10.3389/fonc.2021.819565}, author = {Chang, Hang and Yang, Xu and Moore, Jade and Liu, Xiao-Ping and Jen, Kuang-Yu and Snijders, Antoine M and Ma, Lin and Chou, William and Corchado-Cobos, Roberto and Garc{\'\i}a-Sancha, Natalia and Mendiburu-Eli{\c c}abe, Marina and Perez-Losada, Jesus and Barcellos-Hoff, Mary Helen and Mao, Jian-Hua} } @article {177, title = {Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type.}, journal = {Cancer Cell}, volume = {19}, year = {2011}, month = {2011 May 17}, pages = {640-51}, abstract = {

Tissue microenvironment is an important determinant of carcinogenesis. We demonstrate that ionizing radiation, a known carcinogen, affects cancer frequency and characteristics by acting on the microenvironment. Using a mammary chimera model in which an irradiated host is transplanted with oncogenic Trp53 null epithelium, we show accelerated development of aggressive tumors whose molecular signatures were distinct from tumors arising in nonirradiated hosts. Molecular and genetic approaches show that TGFβ mediated tumor acceleration. Tumor molecular signatures implicated TGFβ, and genetically reducing TGFβ abrogated the effect on latency. Surprisingly, tumors from irradiated hosts were predominantly estrogen receptor negative. This effect was TGFβ independent and linked to mammary stem cell activity. Thus, the irradiated microenvironment affects latency and clinically relevant features of cancer through distinct and unexpected mechanisms.

}, keywords = {Animal, Animals, Breast Neoplasms, Cell Transformation, Dose-Response Relationship, Epithelial Cells, Estrogen, Female, Gene Expression Profiling, Gene Expression Regulation, Gene Regulatory Networks, Inbred BALB C, Knockout, Mammary Glands, Mice, Neoplasms, Neoplastic, Radiation, Radiation Chimera, Radiation-Induced, Reaction Time, Receptors, Time Factors, Transforming Growth Factor beta1, Tumor Burden, Tumor Microenvironment, Tumor Suppressor Protein p53, Whole-Body Irradiation}, issn = {1878-3686}, doi = {10.1016/j.ccr.2011.03.011}, author = {Nguyen, David H and Oketch-Rabah, Hellen A and Illa-Bochaca, Irineu and Geyer, Felipe C and Reis-Filho, Jorge S and Jiang-Hua Mao and Ravani, Shraddha A and Zavadil, Jiri and Borowsky, Alexander D and Jerry, D Joseph and Dunphy, Karen A and Seo, Jae Hong and Haslam, Sandra and Medina, Daniel and Barcellos-Hoff, Mary Helen} } @article {88, title = {Multidimensional profiling of cell surface proteins and nuclear markers}, journal = {IEEE/ACM Trans Comput Biol Bioinform}, volume = {7}, year = {2010}, month = {2010 Jan-Mar}, pages = {80-90}, abstract = {

Cell membrane proteins play an important role in tissue architecture and cell-cell communication. We hypothesize that segmentation and multidimensional characterization of the distribution of cell membrane proteins, on a cell-by-cell basis, enable improved classification of treatment groups and identify important characteristics that can otherwise be hidden. We have developed a series of computational steps to 1) delineate cell membrane protein signals and associate them with a specific nucleus; 2) compute a coupled representation of the multiplexed DNA content with membrane proteins; 3) rank computed features associated with such a multidimensional representation; 4) visualize selected features for comparative evaluation through heatmaps; and 5) discriminate between treatment groups in an optimal fashion. The novelty of our method is in the segmentation of the membrane signal and the multidimensional representation of phenotypic signature on a cell-by-cell basis. To test the utility of this method, the proposed computational steps were applied to images of cells that have been irradiated with different radiation qualities in the presence and absence of other small molecules. These samples are labeled for their DNA content and E-cadherin membrane proteins. We demonstrate that multidimensional representations of cell-by-cell phenotypes improve predictive and visualization capabilities among different treatment groups, and identify hidden variables.

}, keywords = {Biological, Cadherins, Cell Membrane, Cell Nucleus, Computer Simulation, DNA, Gene Expression Profiling, Membrane Proteins, Models}, issn = {1557-9964}, doi = {10.1109/TCBB.2008.134}, author = {Ju Han and Hang Chang and Andarawewa, Kumari and Yaswen, Paul and Barcellos-Hoff, Mary Helen and Parvin, Bahram} }