The Cell of Origin of Breast Cancer -- Stem Cells, Progenitor Cells or More Differentiated Cells?
Tumor cells are similar to stem cells in many aspects, including incomplete differentiation status, high proliferation potential, capacity for self-renewal, ability to migrate, and expression of stem cell markers; consequently, cancers were thought to arise from stem cells that are blocked from normal differentiation. This theory has been supported in the case of teratocarcinomas, and it is generally accepted for colorectal cancer. In the breast, it has been hypothesized that hormone-induced cell differentiation of stem cells is a contributing factors for the reduced risk of breast cancer in women who have their first full-term pregnancy early in life. However, the exact cell of origin of breast cancer is still unclear. The goal of this project is introduce oncogenic mutations selectively into specific cell subsets (stem cells, various progenitors, and various differentiated cells) in the mouse mammary gland, and to learn about their responses to these oncogenic mutations. Besides cell subsets in the normal mammary tissue, these mutated genes will also be introduced into different cell subsets in precancerous early lesions to gain insight into how the cellular heterogeneity in the early lesions contributes to the eventual malignancy. The data from these studies may have a profound impact on understanding breast cancer evolution, cellular and genetic heterogeneity, and cancer spread. The results may also suggest novel approaches for cancer prevention and may provide better preclinical models for screening new targeted therapeutics.
The issue of cancer cell of origin cannot be studied conclusively in cultured cells and has been addressed in vivo. However, conventional transgenic and knockout mouse models do not usually have the precision for expression of oncogenic mutations in selected cell subsets. However, as detailed in the last section of this page, the Li lab has pioneered the RCAS-TVA technology for expression of oncogenes in distinct mammary cell subsets. This technique is used widely in the Li lab to address questions in this project and several projects that are described below.
LGR4 Signaling in Breast Cancer Metastasis and Cancer Stem Cells
LGR4, LGR5, and LGR6 comprise a group of proteins in the leucine-rich repeat-containing G-protein-coupled receptors (LGR). They are known to play important and non-redundant roles in development, stem cells, and cancer. LGR4 is highly expressed in the basal-like breast cancer (BLBC), the most aggressive subtype of breast cancer that lacks targeted therapy. There is evidence that LGR4 participates in the formation and progression of BLBCs; however, how LGR4 is causally involved in BLBC and cancer stem cells is unclear. The goal of this project is to establish the molecular mechanisms by which LGR4 regulates breast cancer metastasis and cancer stem cells. Cutting edge technologies include mass-spectrometry, reverse phase protein array, RNA-seq, and advanced mouse models will be used. This work has important implications in understanding molecular regulation of the progression of basal-like breast cancer and may lead to novel therapeutics in treating basal-like tumors with high LGR4 expression.
Formation and Breakdown of Anticancer Barriers (Apoptosis and Senescence) in Breast Tumorigenesis
Premalignant lesions (such as atypia) of the breast sometimes but not always progress to invasive cancer. What causes this small subset of premalignant lesions to progress is poorly understood. Studies in several tissue types indicate that apoptosis and senescence are activated in human premalignant lesions as a result of oncogene over-expression and/or oncogene-induced aberrant proliferation, providing barriers to progression to malignancy. These barriers must be overcome for early lesions to develop into full-blown cancer. However, how these barriers are initially formed in precancerous early lesions and how they are broken in the progression to cancer remain unclear. The goal of this project is to elucidate these barriers at the molecular levels and to identify the key molecular pathways underlying the formation and regulation of these barriers. Some of the key molecules studied in this project include ATM, CHK2, p53, ARF, JAK, STAT, and BCL family members. The impact of this project includes a better understanding of cancer initiation and potential new approaches in breast cancer prevention. (Please read the next two projects for this translational implication.)
Preventing Breast Cancer in Women on Antipsychotics
There is a large population of breast cancer high-risk women who are also on antipsychotics (neuroleptics) in the U.S. Antiestrogen treatment is the only FDA-approved therapy for preventing breast cancer. It requires prolonged and continuous treatment and can have significant side-effects. Therefore, it is not widely used in this vulnerable population of women. The overall goal of this project is to identify an effective chemoprevention approach that requires only a short-term treatment for women on antipsychotics.
The use of antipsychotics is often associated with an abnormal increase of serum prolactin which can activate JAK2-STAT5 signaling. Therefore, the specific goal of this project is to test whether antipsychotics activate JAK2-STAT5 signaling in preexistent early precancerous lesions in the breast, and to investigate whether intermittent treatment to block JAK2-STAT5 activity can effectively prevent breast cancer in high-risk women on antipsychotics. This proposed study will establish the roles of PRL-JAK2-STAT5 in breast cancer risk in women on antipsychotics, and may lead to a realistic prevention method for a large population of high-risk women on antipsychotics.