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

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-SRLB-Q (M1))
Program Officer
Marks, Cheryl L
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Schools of Medicine
Saint Louis
United States
Zip Code
Mori, Hidetoshi; Cardiff, Robert D; Borowsky, Alexander D (2018) Aging Mouse Models Reveal Complex Tumor-Microenvironment Interactions in Cancer Progression. Front Cell Dev Biol 6:35
Mori, Hidetoshi; Chen, Jane Q; Cardiff, Robert D et al. (2017) Pathobiology of the 129:Stat1 -/- mouse model of human age-related ER-positive breast cancer with an immune infiltrate-excluded phenotype. Breast Cancer Res 19:102
Ward, Jeffrey P; Gubin, Matthew M; Schreiber, Robert D (2016) The Role of Neoantigens in Naturally Occurring and Therapeutically Induced Immune Responses to Cancer. Adv Immunol 130:25-74
Schmitz, Jennifer; Schwab, Julian; Schwenck, Johannes et al. (2016) Decoding Intratumoral Heterogeneity of Breast Cancer by Multiparametric In Vivo Imaging: A Translational Study. Cancer Res 76:5512-22
Bao, Lei; Cardiff, Robert D; Steinbach, Paul et al. (2015) Multipotent luminal mammary cancer stem cells model tumor heterogeneity. Breast Cancer Res 17:137
Gubin, Matthew M; Artyomov, Maxim N; Mardis, Elaine R et al. (2015) Tumor neoantigens: building a framework for personalized cancer immunotherapy. J Clin Invest 125:3413-21
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
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
Chen, Jane Q; Mori, Hidetoshi; Cardiff, Robert D et al. (2015) Abnormal Mammary Development in 129:STAT1-Null Mice is Stroma-Dependent. PLoS One 10:e0129895
Hou, Kirk K; Pan, Hua; Schlesinger, Paul H et al. (2015) A role for peptides in overcoming endosomal entrapment in siRNA delivery - A focus on melittin. Biotechnol Adv 33:931-40

Showing the most recent 10 out of 28 publications