Despite recent improvements in mortality for breast cancer patients, it is still not known why many patients relapse even after an initial response to conventional endocrine and/or chemotherapies. We have approached this question using both genetically engineered mouse models and in patients in the clinic. Using a unique transplantable p53 null mammary tumor model we have identified a highly enriched Tumor-Initiating Cell (TIC) subpopulation. Both in vitro and in vivo experiments indicate that more efficient DNA damage repair mechanisms exist in these TICs as compared to the bulk of the tumor cells. In parallel studies, an epithelial- mesenchymal transition(EMT)-related gene signature was identified in TICs isolated from breast cancer patients. This signature was present in the subset of human breast cancers characterized as """"""""claudin-low"""""""", and most importantly was significantly enriched in patients who failed both hormonal and chemotherapy. Often TICs represent a small subpopulation of cells within a tumor, but """"""""claudin-low"""""""" tumors of both mice and humans appear to be highly enriched in TICs. TICs may be intrinsically more resistant to DNA damage induced by radiation and chemotherapy treatments, thus in part explaining their resistance to conventional treatments;they have also been suggested to be responsible for metastatic dissemination, tumor dormancy and recurrence. Thus, to help elucidate the mechanisms and signaling pathways that are responsible for the intrinsic therapeutic resistance of TICs, and to develop therapies that can overcome this resistance to conventional treatments, the following Specific Aims are proposed:
Aim 1. Analysis of TICs in the different subtypes of the murine p53 null tumors including the claudin- low/spindloid class.
Aim 2. To determine if perturbation of EMT pathways in the p53 null claudin-low/spindloid tumors alters their phenotypic properties.
Aim 3. To determine the therapeutic sensitivity of TICs. One pressing need to effectively target breast cancer tumor initiating cells is the development of improved preclinical models to test these therapies. To address this need, we have identified mouse models that develop claudin-low/spindloid tumors, where the bulk of the tumors cells appear to be TICs. Thus, we believe that we have an appropriate and validated model for the investigation of important signaling pathways and therapeutics. This multiPI grant combines the considerable stem cell and signaling pathway expertise in the Rosen laboratory with the genomics, bioinformatics and therapeutics expertise in the Perou laboratory and, therefore represents an excellent synergy between the two. )

Public Health Relevance

Despite recent improvements in mortality for breast cancer patients, it is still not known why many patients relapse even after an initial response to conventional endocrine and/or chemotherapies. To effectively target breast cancer tumor initiating cells thought to be responsible for intrinsic therapeutic resistance and recurrence, we have identified preclinical mouse models that develop claudin-low/spindloid tumors, where the bulk of the tumors cells appear to be tumor initiating cells. These now provide novel models for the elucidation of critical signaling pathways and therapeutics required to eliminate these cells.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA148761-05
Application #
8595295
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2010-03-17
Project End
2014-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
5
Fiscal Year
2014
Total Cost
$437,794
Indirect Cost
$86,536
Name
Baylor College of Medicine
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Pfefferle, Adam D; Agrawal, Yash N; Koboldt, Daniel C et al. (2016) Genomic profiling of murine mammary tumors identifies potential personalized drug targets for p53-deficient mammary cancers. Dis Model Mech 9:749-57
Dennison, Jennifer B; Shahmoradgoli, Maria; Liu, Wenbin et al. (2016) High Intratumoral Stromal Content Defines Reactive Breast Cancer as a Low-risk Breast Cancer Subtype. Clin Cancer Res 22:5068-5078
Becker, Marc A; Ibrahim, Yasir H; Oh, Annabell S et al. (2016) Insulin Receptor Substrate Adaptor Proteins Mediate Prognostic Gene Expression Profiles in Breast Cancer. PLoS One 11:e0150564
Welte, Thomas; Kim, Ik Sun; Tian, Lin et al. (2016) Oncogenic mTOR signalling recruits myeloid-derived suppressor cells to promote tumour initiation. Nat Cell Biol 18:632-44
He, Zhijian; Wan, Xiaomeng; Schulz, Anita et al. (2016) A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 101:296-309
Toneff, M J; Sreekumar, A; Tinnirello, A et al. (2016) The Z-cad dual fluorescent sensor detects dynamic changes between the epithelial and mesenchymal cellular states. BMC Biol 14:47
Usary, Jerry; Darr, David Brian; Pfefferle, Adam D et al. (2016) Overview of Genetically Engineered Mouse Models of Distinct Breast Cancer Subtypes. Curr Protoc Pharmacol 72:14.38.1-11
Silva, Grace O; He, Xiaping; Parker, Joel S et al. (2015) Cross-species DNA copy number analyses identifies multiple 1q21-q23 subtype-specific driver genes for breast cancer. Breast Cancer Res Treat 152:347-56
Prat, Aleix; Fan, Cheng; Fernández, Aranzazu et al. (2015) Response and survival of breast cancer intrinsic subtypes following multi-agent neoadjuvant chemotherapy. BMC Med 13:303
Knezevic, J; Pfefferle, A D; Petrovic, I et al. (2015) Expression of miR-200c in claudin-low breast cancer alters stem cell functionality, enhances chemosensitivity and reduces metastatic potential. Oncogene 34:5997-6006

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