Prospective identification of the pre-cancer stem cell

Ductal Carcinoma In Situ (DCIS) is considered the earliest form of breast cancer where cells that appear malignant develop into benign heterogneous lesions confined within the epithelial membrane, yet progression to invasive ductal carcinoma frequently occurs. Therefore, treatment of the disease is equal to preventing development of invasive cancer. It has previously been suggested that the cells of DCIS may already be programmed to become invasive, which led to the speculation that a small population of cancer stem cells, sharing characteristics with normal stem cells, are responsible for the development of invasive cancer. As a mammary gland stem cell population that increases in size with tumor progression has previously been identified using FACS, along with transplantation experiments revealing a capability to regenerate the ductal tree, the goal of this project was to identify the pre-cancer stem cell population using a mouse model representative of human DCIS and previously established surface markers CD24, CD29 and CD49f. However, identification of the pre-cancer stem cells in the DCIS mouse model using the aforementioned surface markers was proven unsuccessful, and thus novel markers CD44 and CD61 were added to the selectional process to increase specificity. The results of this study revealed a putative stem cell population with a CD24low CD29high CD49fhigh expression profile within mammary glands of normal FVB mice as well as in the pre-cancer mouse model. The data further revealed an increased expression of CD44 in the same population, with respect to the DCIS mouse model as well as in normal mammary glands. However, CD61 expression was increased in a CD24negative CD29low CD49flow population, indicating a possible luminal epithelial origin. The results furthermore revealed an increase in the stem cell population with carcinoma progression through comparisons of DCIS lesions, DCIS derived tumors and a tumor cell line. In summary, the results of this study indicates that a pre-cancer stem cell population may be distinguished based on the expression of surface markers CD24, CD29, CD49f and CD44, and seems to correlate with their expansion and progression to invasive cancer. These findings should significantly improve the isolation of the pre-cancer stem cell population in DCIS, and thus may lead to new treatments aimed at eliminating the cancer stem cells.