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.
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.
|D'Angelo, Rosemarie C; Ouzounova, Maria; Davis, April et al. (2015) Notch reporter activity in breast cancer cell lines identifies a subset of cells with stem cell activity. Mol Cancer Ther 14:779-87|
|Brooks, Michael D; Burness, Monika L; Wicha, Max S (2015) Therapeutic Implications of Cellular Heterogeneity and Plasticity in Breast Cancer. Cell Stem Cell 17:260-71|
|Brooks, Michael D; Wicha, Max S (2015) Tumor twitter: cellular communication in the breast cancer stem cell niche. Cancer Discov 5:469-71|
|Luo, Ming; Brooks, Michael; Wicha, Max S (2015) Epithelial-mesenchymal plasticity of breast cancer stem cells: implications for metastasis and therapeutic resistance. Curr Pharm Des 21:1301-10|
|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|
|Liu, Suling; Cong, Yang; Wang, Dong et al. (2014) Breast cancer stem cells transition between epithelial and mesenchymal states reflective of their normal counterparts. Stem Cell Reports 2:78-91|
|Murlidhar, Vasudha; Zeinali, Mina; Grabauskiene, Svetlana et al. (2014) A radial flow microfluidic device for ultra-high-throughput affinity-based isolation of circulating tumor cells. Small 10:4895-904|
|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|
|Korkaya, Hasan; Wicha, Max S (2013) HER2 and breast cancer stem cells: more than meets the eye. Cancer Res 73:3489-93|
|Azizi, Ebrahim; Wicha, Max S (2013) Point: cancer stem cells--the evidence accumulates. Clin Chem 59:205-7|
Showing the most recent 10 out of 45 publications