beta-catenin signaling in mammary gland development and tumorigenesis

Recent evidence has shown that breast tumors arise from, and can be propagated by, a minority of cells, termed tumor initiating or cancer stem cells. Wnt/beta-catenin signaling is deregulated in human breast cancer and in several other human cancers including skin cancer, colon cancer, and leukemia. In the latter three tissues, Wnt/beta-catenin signaling has been shown to accompany and regulate stem/progenitor cell proliferation and maintenance. Canonical Wnt/beta-catenin signaling is essential for embryonic and adult mammary development. Mice expressing stabilized beta-catenin (MMTV-DeltaN89beta-catenin) develop mammary adenocarcinomas at an early age. Appearance of these tumors is preceded by precocious alveolar development, suggesting a connection between activation of pathways controlling alveologenesis and predisposition to breast cancer. Using mice carrying reporters of beta-catenin signaling, I have identified beta-catenin signaling cells in the mammary glands and tumors of MMTV-DeltaN89beta-catenin mice. A subset of luminal cells undergoing beta-catenin signaling in MMTV-DeltaN89beta-catenin glands give rise to mammary hyperplasias, structures from which the tumors are thought to arise. The majority of beta-catenin signaling cells within tumors display a CD24+/hiCD49flow profile, identical to that described for a population of normal mammary cells with progenitor characteristics. Functional analysis of beta-catenin signaling cells isolated from MMTV-DeltaN89beta-catenin tumors demonstrated their enhanced colony forming capability and functional bipotency, suggesting that the tumorigenic potential of MMTV-DeltaN89beta-catenin tumors may reside within these cells. A comparison to the stem cell marker profile and beta-catenin reporter expression of MMTV-Wnt1 tumors revealed that beta-catenin signaling cells in this model are distinct from those of MMTV-DeltaN89beta-catenin tumors and may represent a more primitive cancer cell. These results suggest that mammary tumors caused by deregulated beta-catenin signaling may arise from two distinct tumor initiating cells.