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Identification of breast tumor initiating cells by generation of mice overexpressing HER2 and Wnt-1 in ERalpha-positive cells
The most important challenge in developing new therapies for breast cancer is the lack of knowledge of the tumor initiating cancer cell. Breast cancer is a genetically and clinically heterogeneous disease. It is unclear whether different target cells contribute to this heterogeneity and which cell types are most susceptible to oncogenesis. Several morphologically distinct cell populations have been identified in the mammary gland; therefore, the cellular origin of breast cancer has been controversial. It is still technically challenging to directly ask whether breast cancers arise from stem cells or their more differentiated progeny. However, studies in the epidermis and the hematopoietic system have demonstrated that cancers that arise from stem or progenitor cells usually express markers of the originating cells. Invasive breast cancers can be divided into two subtypes based on whether or not the tumor cells express estrogen receptors (ERs) in their nuclei . Therefore, our goal is to examine whether oncoprotein activation specifically in ERa-positive cells results in mammary neoplasia in mice. We hypothesize that the ERa-positive mammary cells are key targets of transformation. To begin to address this issue, we will use a baculovirus clone -mediated targeting system we have recently generated that allows expression specifically in ERa-positive cells in transgenic mice. The specific aims are as follows: 1. To create baculovirus vectors that have well characterized oncoproteins HER2 and Wnt-1 expressed under the ERa promoter. 2. To generate mice that express HER2 and Wnt-1 specifically in the ERa-positive cells. The mice will be analyzed for spontaneous and carcinogen-induced tumor susceptibility. We predict that the HER2 model will produce ERa-positive tumors and Wnt-1, acting in a paracrine manner to induce proliferation, will produce ERa-negative tumors. The identification and characterization of tumor initiating cells will offer important information in developing new therapies for breast cancer.
Only a small subset of cells within a tumor possesses the capacity to proliferate and form new tumors. It has been suggested that human breast cancers arise from transformation of early stem or progenitor cells. These cells are specialized cells that generate progeny for organ formation and maintenance. They can be found within the different tissues of the human body at all stages of life. The current challenge is to develop therapies that selectively affect the cancer stem cells or tumor initiating cells while sparing normal cells. Proliferation of breast cells is dependent on the regulatory action of steroid hormones, estrogen and progesterone, and growth factors. The physiological response of estrogen is mediated by its receptor ER. During development, the receptor is expressed in a subset of scattered, non-proliferating epithelial cells regulating proliferation of neighboring cells. These ER-positive cells are a likely target for transformation; two thirds of human breast tumors have a high proportion of ER-positive cells. Because transformations can be caused by overexpression of oncoproteins, we have generated a system to express proteins specifically in ERa-positive cells in mice. We propose to utilize this system to examine whether oncoprotein activation in ERa-positive cells in mice leads to spontaneous or carcinogen-induced tumor formation. We hypothesize that ERa-positive cells function in tumor initiation and that both ERa-positive and negative tumors will develop in our mouse models. The identification and characterization of tumor initiating cells will offer important information in developing new therapies for breast cancer.