Research Projects
Stem Cells and Breast Cancer
Tumor cells are similar to stem and progenitor cells in many aspects, including incomplete differentiation status, high proliferation potential, capacity for self-renewal, ability to migrate, and expression of stem and progenitor cell markers; consequently, cancers are thought to arise from stem and progenitor cells that are blocked from normal differentiation. This theory has been supported in the case of teratocarcinomas, and it is generally accepted for several types of leukemias. It has been hypothesized that hormone-induced differentiation and possible loss of progenitor cells, associated with pregnancy, are contributing factors for the reduced risk of breast cancer in women who have their first full-term pregnancy early in life.
Current mouse models do not carry oncogenic lesions specifically in stem or progenitor cells. Cancers arising from these cells may more closely resemble human breast cancers. We are using novel methods, including the TVA technology, to induce tumorigenesis from this subset of mammary cells in hopes of defining the originating cell of breast cancer and producing high fidelity mouse models for preclinical testing of novel therapeutic agents.
Wnt Signaling and Breast Cancer
Wnt signaling is activated in many cancer types including breast cancer. The activation of Wnt-1 by retroviral insertion leads to mammary tumors in mice. We investigate how Wnt signaling interacts with other signaling pathways such the Neu-Pten-Akt pathway to induce breast cancer from normal mammary epithelial cells using mouse models and the TVA technology (see below).
The Origin of ER– and ER+ Breast Cancers
Breast cancers are thought to evolve through the tumor promotional effects of estrogen and from genetic alterations that accumulate in normal ductal cells, 30 percent of which express estrogen receptor (ER + ). In some women, these changes lead to hyperplasias (ER + in the majority of cells), in situ cancer and then invasive and metastatic diseases. There are two therapeutically distinct types of breast cancers in humans, those (70-75 percent) expressing estrogen receptor in a fraction of the tumor cells (ER + ), and those lacking ER (ER – ). However, the cellular and molecular mechanisms leading to these phenotypes are unclear. We hope to use novel methods, such as the TVA technology (see below) and the Cre-mediated cell lineage tracing approach, to determine whether causal genetic lesions and/or the ER status of the initiating cell determines whether the resultant cancer expresses ER.
TVA Gene Delivery System
We use this novel method for our reserch. This system offers flexible gene transfer to somatic cell in vivo. It is based on the use of a modified sub-group A avian leukosis virus vector (RCAS) to carry exogenous genes to specific mouse cells that are made susceptible to infection by the expression of TVA, the receptor for RCAS( 20 ). Since mammalian cells lack this receptor, they are not normally susceptible to infection by RCAS; however, ectopic expression of TVA (e.g by a tissue-directed transgene) transforms an otherwise resistant cell type to a susceptible one. Since the exogenous gene is expressed from the viral LTR and is no longer dependent upon the transgenic promoter, the expression of the gene of interest remains largely constant even if the infected cells start to take a new direction in their differentiation. An added advantage is that this method provides oncogenes to individual mammary cells in a “field” of normal cells, recapitulating how cancer evolves in humans ( 20 ). Please visit the TVA site for more information on this innovative technology. For its application in the mammary gland, please download our recent publication in PNAS.