The epithelial components of the mammary gland arise from stem cells that have the capacity for self- renewal as well as multi-lineage differentiation. Recent studies have provided support for the """"""""cancer stem cell hypothesis"""""""", which holds that these cells or their immediate progeny may be targets for mammary carcinogenesis which results from disregulation of stem cell self-renewal pathways. This results in expanded stem cell populations which are the targets for further carcinogenic events. Resulting tumors consist of heterogeneous cell populations driven by a stem cell component that maintains the ability to self-renew as well as to differentiate into cells that comprise the bulk of the tumor. We have developed techniques for the isolation and characterization of stem cells from both human mammary glands and mammary tumors. Furthermore, we have demonstrated that stem cell markers such as aldehyde hydrogenase 1 may be utilized to detect mammary stem cells in situ in formalin fixed paraffin embedded tissue. We propose to utilize these new tools to directly test a key component of the """"""""cancer stem cell hypothesis"""""""" regarding the cellular origin and early molecular events which leads to human breast carcinogenesis. We propose that a common biological link between hereditary and sporadic breast cancer is that both may be initiated by disregulation of mammary stem cell self-renewal pathways. In hereditary breast cancer, this may involve deletion of BRCA-1, whereas in sporadic breast cancers, disregulation of genes such as HER-2 and PTEN result in clonal stem cell expansion providing targets for secondary transforming events. In order to test these hypotheses, we propose to utilize both in vitro systems and a humanized mouse xenograft model, as well as in situ approaches developed by our laboratory to elucidate the roles of BRCA-1, HER-2 and PTEN in the regulation of mammary stem cell self-renewal and carcinogenesis. These studies may lead to new approaches for the early detection and prevention of breast cancer.

Public Health Relevance

Breast cancer is the most common malignancy in women and the 2nd leading cause of cancer death. Since breast cancer may originate in normal breast stem cells, understanding the earliest changes in these cells during cancer formation is critical for the development of novel strategies to detect and prevent this cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA129765-02
Application #
7582399
Study Section
Cancer Molecular Pathobiology Study Section (CAMP)
Program Officer
Watson, Joanna M
Project Start
2008-04-01
Project End
2013-01-31
Budget Start
2009-02-01
Budget End
2010-01-31
Support Year
2
Fiscal Year
2009
Total Cost
$307,398
Indirect Cost
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
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Nagarsheth, Nisha; Wicha, Max S; Zou, Weiping (2017) Chemokines in the cancer microenvironment and their relevance in cancer immunotherapy. Nat Rev Immunol 17:559-572
Dobrolecki, Lacey E; Airhart, Susie D; Alferez, Denis G et al. (2016) Patient-derived xenograft (PDX) models in basic and translational breast cancer research. Cancer Metastasis Rev 35:547-573
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
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
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 14:779-787
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
Lombardi, Sara; Honeth, Gabriella; Ginestier, Christophe et al. (2014) Growth hormone is secreted by normal breast epithelium upon progesterone stimulation and increases proliferation of stem/progenitor cells. Stem Cell Reports 2:780-93
Deng, Lu; Shang, Li; Bai, Shoumin et al. (2014) MicroRNA100 inhibits self-renewal of breast cancer stem-like cells and breast tumor development. Cancer Res 74:6648-60

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