We have developed a novel mouse model of estrogen receptor-alpha positive (ER?+) mammary cancer in STAT1-/- mice that shows remarkable resemblance to ER?+ luminal breast cancer in humans. A key feature of this model is that primary tumor cells from these mice- are >90% positive for ER? and progesterone receptors (PR) and show estrogen growth dependency in vitro and in vivo. On the basis of gene expression profiling, the mammary tumor cells that develop in STAT1-/- mice show extraordinary similarity to human luminal breast cancers. Developmentally this model also faithfully recapitulates the natural history of human luminal breast cancer, including the capacity to progress to ovarian hormone independence. Thus, our model fills a long-standing need for a suitable mouse model of the most common form of human breast cancer. In this U0l application, we propose to capitalize on this model to learn more about the origins and progression of luminal breast cancers, and to develop novel therapies that can be translated to humans. We have assembled a multi-disciplinary, multi-institutional research team to pursue the following four Specific Aims using state-of-the-art technologies.
In Specific Aim 1 we will complete the characterization of ER?+ (luminal) mammary tumors from STAT1-/- mice, placing special emphasis on defining the role(s) of the hyperactivated JAK2-STAT3/5 signaling pathway that is operative in these tumor cells, and in identifying differentially expressed proteins on ER?+ mammary tumor cell surfaces that are either responsible for the dysregulated JAK2-STAT3/5 signaling or might be used to target imaging agents or therapeutics directly to the tumor.
In Specific Aim 2 we will define the changes that occur in ER? expression/signaling, JAK2-STAT3/5 signaling and gene expression in STAT1-/- ER?+ (luminal) mammary tumors that grow out following ovariectomy of tumor bearing mice, and explore the underlying mechanisms for this progression.
In Specific Aim 3 we will use micro-positron emission tomography (microPET) imaging to identify functionally important changes in ER? expression/function, expression of tumor cell surface markers and cellular metabolism/proliferation of ER?+ (luminal) mammary tumors in STAT1-/- mice before and after ovariectomy, and explore whether microPET can be used as a surrogate marker of therapeutic efficacy. Finally, in Specific Aim 4 we will develop novel combinatorial tumor-targeted therapies to effectively treat mice bearing naturally arising and transplanted mouse ER?+ (luminal) mammary cancers with the hope of translating our findings into new treatments for human breast cancer
|Chan, S R; Rickert, C G; Vermi, W et al. (2014) Dysregulated STAT1-SOCS1 control of JAK2 promotes mammary luminal progenitor cell survival and drives ER*(+) tumorigenesis. Cell Death Differ 21:234-46|
|Gubin, Matthew M; Zhang, Xiuli; Schuster, Heiko et al. (2014) Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515:577-81|
|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; Borowsky, Alexander D (2014) At last: classification of human mammary cells elucidates breast cancer origins. J Clin Invest 124:478-80|
|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|
|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|
|Hou, Kirk K; Pan, Hua; Ratner, Lee et al. (2013) Mechanisms of nanoparticle-mediated siRNA transfection by melittin-derived peptides. ACS Nano 7:8605-15|
|Vesely, Matthew D; Schreiber, Robert D (2013) Cancer immunoediting: antigens, mechanisms, and implications to cancer immunotherapy. Ann N Y Acad Sci 1284:1-5|
|Hou, Kirk K; Pan, Hua; Lanza, Gregory M et al. (2013) Melittin derived peptides for nanoparticle based siRNA transfection. Biomaterials 34:3110-9|
|Couto, S S; Bolon, B; Cardiff, R D (2012) Morphologic manifestations of gene-specific molecular alterations ("genetic addictions") in mouse models of disease. Vet Pathol 49:116-29|
Showing the most recent 10 out of 11 publications