The natural history of human breast cancer is characterized by the progressive selection and outgrowth of cells that possess increasingly aggressive properties. Among these properties, the ability to metastasize is the most important determinant of clinical outcome since metastatic breast cancer is, at present, an incurable disease. For most types of human cancer, residual tumor cells remain following treatment that are not detected by conventional clinical testing. In the case of breast cancer, disseminated tumor cells are typically present at the time of diagnosis and have the ability to survive in a dormant state within tissues for extended periods of time, either as solitary cells or as micrometastases, and then emerge from dormancy and resume growth at a later date. As such, metastasis, tumor dormancy, and recurrence constitute fundamental clinical manifestations of tumor progression that collectively are responsible for the vast majority of breast cancer deaths. Nevertheless, while these aspects of tumor progression are of unrivaled clinical importance, the mechanisms underlying them are largely unknown. Accordingly, the principal goal of this Mouse Models of Human Cancer Consortium (MMHCC) application is to develop new conceptual and technical approaches to understanding the mechanisms responsible for breast cancer metastasis, dormancy, and recurrence. To accomplish this, state-of-the-art molecular, genetic, genomic, cellular, and intravital imaging methods will be used to interrogate a series of well-validated genetically engineered mouse models for breast cancer progression developed by the investigators of this program. This application represents a highly integrated, multidisciplinary effort to understand critical aspects of tumor progression and breast cancer biology by senior investigators from the University of Pennsylvania, the Albert Einstein College of Medicine, McGill University, and the University of California, Davis. By elucidating the biology of breast cancer progression, this MMHCC program can accelerate the development of more effective approaches to detecting, arresting, and eradicating disseminated tumor cells.
At the time of diagnosis, women with breast cancer often already have tumor cells that have disseminated to distant sites. Following surgery, chemotherapy, and radiation therapy, these cells can survive in what is believed to be a dormant state and linger unrecognized for more than a decade before emerging as recurrent cancers. Consequently, breast cancers that appear cured may resurface 10 or 20 years later. Since breast cancer mortality is usually due to metastasis, tumor dormancy, and recurrence, the ability to model these processes in mice and study these rare dormant tumor cells could markedly accelerate the development of more effective approaches to treating breast cancer patients.
|Bao, Lei; Cardiff, Robert D; Steinbach, Paul et al. (2015) Multipotent luminal mammary cancer stem cells model tumor heterogeneity. Breast Cancer Res 17:137|
|Mori, Hidetoshi; Soonsawad, Pan; Schuetter, Louis et al. (2015) Introduction of Zinc-salt Fixation for Effective Detection of Immune Cell-related Markers by Immunohistochemistry. Toxicol Pathol 43:883-9|
|Engelberg, Jesse A; Retallack, Hanna; Balassanian, Ronald et al. (2015) "Score the Core" Web-based pathologist training tool improves the accuracy of breast cancer IHC4 scoring. Hum Pathol 46:1694-704|
|Payne, Ania W; Pant, Dhruv K; Pan, Tien-Chi et al. (2014) Ceramide kinase promotes tumor cell survival and mammary tumor recurrence. Cancer Res 74:6352-63|
|Feng, Yi; Pan, Tien-Chi; Pant, Dhruv K et al. (2014) SPSB1 promotes breast cancer recurrence by potentiating c-MET signaling. Cancer Discov 4:790-803|
|Engelberg, Jesse A; Giberson, Richard T; Young, Lawrence J T et al. (2014) The use of mouse models of breast cancer and quantitative image analysis to evaluate hormone receptor antigenicity after microwave-assisted formalin fixation. J Histochem Cytochem 62:319-34|
|Cardiff, Robert D; Miller, Claramae H; Munn, Robert J (2014) Analysis of mouse model pathology: a primer for studying the anatomic pathology of genetically engineered mice. Cold Spring Harb Protoc 2014:561-80|
|Alvarez, James V; Belka, George K; Pan, Tien-Chi et al. (2014) Oncogene pathway activation in mammary tumors dictates FDG-PET uptake. Cancer Res 74:7583-98|
|Thiel, Austin T; Feng, Zijie; Pant, Dhruv K et al. (2013) The trithorax protein partner menin acts in tandem with EZH2 to suppress C/EBPÎ± and differentiation in MLL-AF9 leukemia. Haematologica 98:918-27|
|Cardiff, Robert D; Hubbard, Neil E; Engelberg, Jesse A et al. (2013) Quantitation of fixative-induced morphologic and antigenic variation in mouse and human breast cancers. Lab Invest 93:480-97|
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