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Cancer stem cells and tamoxifen resistance
a. Background: Tamoxifen (Tam) is the most prescribed agent targeting estrogen receptor (ER)-positive breast cancer patients. Tam binds ERá and blocks estrogen-dependent growth. The problem is that many patients? cancers are originally sensitive to Tam, but develop hormone resistance and metastatic lesions recur over time. Hormone resistance is a serious problem for these patients. Other investigators have suggested the existence of a breast cancer stem cell that may be at the root of resistance and later metastasis. We have discovered that the SC growth regulator, Dicer, may be a key component of Tam resistance (TR) in breast cancer. Dicer, along with the androgen receptor (AR), is overexpressed in a MCF-7 Tam-resistant cell line that we generated, and they are also both upregulated in metastatic tumors. Dicer is an RNAse III-family nuclease that initiates microRNA interference via processing of microRNAs, and data suggest that microRNAs are required for SCs to bypass growth control. b. Objectives/Hypothesis: I hypothesize that Dicer-overexpressing breast cancer cells are endowed with SC/progenitor cell-like properties, and that combined with AR overexpression, is responsible for the evolution of TR, and tumor-initiating potential. c. Specific Aims: The Aims of this research are: (1) to determine whether Dicer overexpression is associated with SC/progenitor cell properties and TR; (2) to determine whether coexpression of Dicer and AR is associated with evolution to resistance; (3) to determine whether Dicer and/or AR enhance tumor-initiation, and to examine the role of the niche microenvironment in xenograft growth in nu/nu athymic and NOD/SCID mice; (4) to examine whether Dicer expression is associated with resistance in a retrospective clinical study. d. Study Design: We plan to perform in vitro and in vivo experiments to address these Aims including identifying and characterizing the stem-like nature of TR and Dicer-overexpressing cells using side population analysis, flow sorting for CD44/CD24/CK14/CK18 subpopulations, mammosphere growth and in vivo xenograft tumorigenesis in nude and NOD/SCID mice. Additionally, we will perform a retrospective examination of Dicer expression in Tam-resistant and Tam-sensitive tumor specimens. e. Pontential Outcomes and Benefits of the Research: My research will determine the function of Dicer in CSCs, and will determine the relationship of Dicer and AR in TR. The potential for gene-specific therapy within the CSC to eradicate or differentiate the origin of breast cancer is the hallmark of importance represented in this research. Moreover, the potential for development of Dicer and AR biomarker assays that can be used to predict patient response to hormone therapy before or during their treatment are relevant outcomes of my research proposal.
Most women with estrogen receptor-positive breast cancer have been prescribed Tamoxifen (Tam), which binds to the estrogen receptor and blocks estrogen-induced growth. Many patients treated with Tam see an improvement in their condition, but later the cancer comes back. Resistance to Tam is a serious problem and recently it has been proposed that resistance is associated with the existence of cancer stem cells (CSC) which may continue to grow although the patient is being treated. We have discovered that the stem cell (SC) growth regulator, Dicer, may be a key component of hormone resistance in breast cancer. Dicer, along with androgen receptor (AR) levels, is increased in a Tam-resistant breast cancer cell line that we generated, and also in metastatic Tam-resistant tumors from patients with recurrent disease. Dicer processes microRNAs, which are suspected to be involved in promoting SC growth. We hypothesize that Dicer-overexpressing breast cancer cells are endowed with stem cell/progenitor cell-like properties, and that combined with elevated AR expression is responsible for the evolution of tamoxifen resistance (TR), and tumor-initiating potential. Our goals are to determine the stem-like characteristics of Dicer overexpressing cells and define Dicer?s role in TR. Moreover, we will determine if Dicer and AR are functioning together in establishing resistance, and will study the role of Dicer and AR in the formation of tumors in mice. Finally, we will determine if Dicer expression is increased in human Tam-resistant tumor samples. We will use many established methods to determine the stem-like qualities of cells expressing Dicer and AR including culture in vitro and tumor initiation in athymic nude mice. We will analyze a bank of Tam-resistant tumor samples for increased Dicer expression. Our proposal will help to understand the role of Dicer and AR in the clinical obstacle of TR and provide an avenue of potential new treatments for patients with breast cancer.