There is increasing evidence that many human cancers, including breast cancer, are driven and maintained by a cellular subcomponent that displays stem cell properties. These "cancer stem cells" may also mediate tumor metastasis and contribute to treatment resistance and relapse. Our laboratory has identified cellular markers and developed in vitro and mouse models to isolate and characterize normal and malignant human mammary stem cells. We have provided evidence that both hereditary and sporadic breast cancers may be initiated and maintained by dysregulation of pathways that regulate stem cell self-renewal. Furthermore, we have generated preliminary evidence that these cell intrinsic pathways may be modulated by extrinsic factors generated by components of the tumor microenvironment. These factors include a chemokine network which normally functions in tissue inflammation and repair. We propose to test the hypothesis that mammary stromal fibroblasts and mesenchymal stem cells recruited from the bone marrow regulate the self-renewal of normal and malignant breast stem cells. Furthermore, chemokine networks such as the IL-8/CXCR1 axis mediate reciprocal interactions between breast stem cells and their microenvironment. This suggests an important mechanistic link between inflammation and carcinogenesis occurs at the level of chemokine mediated stem cell regulation. We propose to develop a strategy aimed at interfering with interactions between tumor stem cells and other cells in the tumor microenvironment which comprise the stem cell "niche". We will target cancer stem cells through specific blockade of the IL-8/CXCR1 axis utilizing small molecule inhibitors such as repertaxin. Since cancer stem cells may drive tumorigenesis and metastasis as well as contribute to treatment resistance and relapse, the development of novel strategies to target this cell population may lead to improved outcomes for women with advanced breast cancer.

Public Health Relevance

There is increasing evidence that many human cancers, including breast cancer, are driven by a small population of cells that displays stem cell properties. These properties include self-renewal which drives tumorigenesis and differentiation which generates the tumor bulk. Recent in vitro and animal model studies have shown that cancer stem cells, including those of the breast, are relatively resistant to radiation therapy and chemotherapy. There is considerable evidence that the microenvironment regulates normal mammary development as well as tumor growth and metastasis. Since cancer stem cells may drive tumorigenesis and metastasis as well as contributing to treatment resistance and relapse, the development of novel strategies to target this cell population may lead to improved outcomes for women with advanced breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA101860-10
Application #
8464640
Study Section
Tumor Microenvironment Study Section (TME)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2003-07-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
10
Fiscal Year
2013
Total Cost
$230,013
Indirect Cost
$81,137
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Kim, G; Ouzounova, M; Quraishi, A A et al. (2015) SOCS3-mediated regulation of inflammatory cytokines in PTEN and p53 inactivated triple negative breast cancer model. Oncogene 34:671-80
Korkaya, Hasan; Wicha, Max S (2013) Breast cancer stem cells: we've got them surrounded. Clin Cancer Res 19:511-3
Korkaya, Hasan; Wicha, Max S (2013) HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 73:3489-93
Ithimakin, Suthinee; Day, Kathleen C; Malik, Fayaz et al. (2013) HER2 drives luminal breast cancer stem cells in the absence of HER2 amplification: implications for efficacy of adjuvant trastuzumab. Cancer Res 73:1635-46
Azizi, Ebrahim; Wicha, Max S (2013) Point: cancer stem cells--the evidence accumulates. Clin Chem 59:205-7
Wicha, Max S (2013) B4 androgen ablation: attacking the prostate cancer stem cell. J Clin Invest 123:563-5
Conley, Sarah J; Gheordunescu, Elizabeth; Kakarala, Pramod et al. (2012) Antiangiogenic agents increase breast cancer stem cells via the generation of tumor hypoxia. Proc Natl Acad Sci U S A 109:2784-9
Korkaya, Hasan; Liu, Suling; Wicha, Max S (2011) Regulation of cancer stem cells by cytokine networks: attacking cancer's inflammatory roots. Clin Cancer Res 17:6125-9
Korkaya, Hasan; Liu, Suling; Wicha, Max S (2011) Breast cancer stem cells, cytokine networks, and the tumor microenvironment. J Clin Invest 121:3804-9
Liu, Suling; Ginestier, Christophe; Ou, Sing J et al. (2011) Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 71:614-24

Showing the most recent 10 out of 28 publications