Preclinical Modeling of Latent Breast Cancer in Mice

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DESCRIPTION (provided by applicant): Many breast cancer patients suffer relapse years after being rendered free of detectable disease by surgery. This indicates that subclinical malignancy in the form of so-called minimal residual disease (MRD) can persist in these patients and beget disease recurrence. Much of modern breast cancer therapy is directed against MRD (adjuvant treatment) with the goal of preventing relapse. Remarkably, the latent MRD lesions that give rise to breast cancer relapse have never been identified and characterized; therefore, adjuvant treatments have been based on the biology and treatment sensitivity of overt breast cancer. However, the prolonged latency that typically precedes breast cancer relapse indicates that the biology of MRD and that of overt malignancy are distinct. The long-term objective of this application is to provide a biological description of MRD with an emphasis on mechanisms of treatment response. Ultimately, these studies will facilitate more rational approaches to curing breast cancer patients via adjuvant treatment. Genetically modified mice that permit faithful modeling of the clinical behavior of MRD in breast cancer ought to be useful for testing adjuvant treatment strategies and interrogating genetic pathways implicated in mediating treatment response. To model MRD in vivo, transgenic mice that permit reversible activation of an oncogenic Wnt signal in mammary epithelium during any stage of Wnt pathway-initiated mammary tumorigenesis were generated. Following abrogation of oncogenic signaling, established mammary tumors regress leaving long-lived, subclinical MRD lesions with latent malignant potential. Importantly, MRD lesions in this model give rise to tumor relapse after periods of disease latency that provide a window for testing adjuvant treatment strategies. Mice harboring either overt malignancy or MRD lesions will be analyzed under a variety of treatment conditions to test the hypothesis that biological differences between MRD and overt breast cancer impart distinct mechanisms of treatment response and distinct treatment sensitivities to these two forms of neoplasia. The proposed Aims follow. Specific Aim 1: To compare outcomes when employing cytotoxic agents either as primary treatment directed against overt malignancy or as adjuvant treatment directed against MRD. Specific Aim 2: To determine whether inactivation of tumor suppressor loci implicated in mediating cytotoxic treatment responses compromises the cytotoxin-sensitivity of either overt tumors or MRD. Specific Aim 3: To extend our reversible tumorigenesis model to permit study of both overt malignancy and MRD lesions residing at metastatic sites. These studies will provide new insights into the biological behavior of MRD lesions and, thereby, shed new light on the crucial but poorly understood link between primary and relapsed breast cancer.