Author(s): Rebecca Lamb 1,*, Matthew P. Ablett 2, Katherine Spence 2, Göran Landberg 1, Andrew H. Sims 3, Robert B. Clarke 2,*
WNT proteins are a family of secreted, glycosylated, and palmitoylated peptides which function in diverse processes such as embryonic induction, generation of cell polarity, and cell fate specification . Aberrant activation of Wnt signaling has been described in a number of human cancers including colorectal cancer, ovarian cancer and breast cancer , , , , , . [beta]-catenin expression has been associated with poor prognosis in breast cancer patients in a number of studies ,  and is enriched in basal-like breast cancer . Furthermore loss of negative pathway regulators such as the extracellular inhibitor of WNT signaling, secreted Frizzled-related protein 1 (sFRP1 ), is found in many breast tumors and is associated with poor prognosis , . Down regulation of the inhibitor Dickkopf 1 (DKK1 ) in a lung metastases derived MCF7-LM cell line demonstrates the importance of Wnt regulation in the metastatic process in breast cancer . Collectively these data suggest that WNT pathway de-regulation within the breast contributes to cancer formation and metastasis.
Recent studies suggest breast cancer initiation and recurrence may be regulated by a small population of cells within the tumor, either stem cells or cells that exhibit stem-like properties . Transplantation experiments using immunocomprimised mice, showed that as few as 100 human breast cancer cells with the cell surface markers CD44+ CD24-/low were tumorigenic and could be serially passaged to generate new tumours .
Cells isolated from human breast cancers marked by CD44+ CD24-/low lineage are anoikis-resistant and capable of self-renewal as mammosphere (MS) colonies providing a link between MS and cell surface markers that enrich for tumorgenic cells , .
Expression of Wnt1 in human mammary epithelial cells increases stem cell self renewal, resistance to apoptosis and failure to senesce . More recent work using the MMTV-WNT-1 mouse model has identified an expanded mammary stem cell (SC) pool from a population of committed luminal progenitors indicating that Wnt-1 activation induces the appearance of aberrant progenitor cells, and suggest that both mammary stem and progenitor cells can serve as the cellular targets of WNT-1-induced tumorigenesis .
WNT pathway activation increases radio resistance of progenitor cells in the mouse mammary gland and human breast cancer cell lines , , which implicates the WNT pathway in resistance to current anti-cancer therapies, potentially through the regulation of stem and progenitor cell populations.
In this study we investigated the WNT pathway both in whole cell populations and stem-like cells of breast cell lines and patient-derived metastatic breast cancer samples. WNT pathway gene expression correlates with estrogen receptor (ER) expression and molecular sub-type, and some genes predict prognosis. WNT signalling was found to be activated in breast cancer stem-like cells compared to normal stem-like cells. Finally, we show that WNT pathway inhibition preferentially reduces stem-like cell activity in patient-derived metastatic breast cancer compared to normal cells. Collectively, these data suggest potential of...