c-Myc Transforms Human Mammary Epithelial Cells through Repression of the Wnt Inhibitors DKK1 and SFRP1

Abstract

c-myc is frequently amplified in breast cancer; however, the mechanism of myc-induced mammary epithelial cell transformation has not been defined. We show that c-Myc induces a profound morphological transformation in human mammary epithelial cells and anchorage-independent growth. c-Myc suppresses the Wnt inhibitors DKK1 and SFRP1, and derepression of DKK1 or SFRP1 reduces Myc-dependent transforming activity. Myc-dependent repression of DKK1 and SFRP1 is accompanied by Wnt target gene activation and endogenous T-cell factor activity. Myc-induced mouse mammary tumors have repressed SFRP1 and increased expression of Wnt target genes. DKK1 and SFRP1 inhibit the transformed phenotype of breast cancer cell lines, and DKK1 inhibits tumor formation. We propose a positive feedback loop for activation of the c-myc and Wnt pathways in breast cancer.

The SFRP family of WNT inhibitors function as novel tumor suppressor genes epigenetically silenced in medulloblastoma

“…SFRP1 may also be influenced by transcription factor-mediated repression. The MYC transcription factor is known to bind to the SFRP1 promoter region, strongly repressing SFRP1 transcription (Cowling et al, 2007). On the basis of Exon Array data, the top quartile of MYC expressors ('high MYC group') showed reduced SFRP1 expression compared with the bottom quartile of MYC expressors ('low MYC group') ( Figure 3d).…”

New model systems provide insights into Myc-induced transformation

“…A comprehensive evaluation of the ability of ectopic Myc to enhance transformation throughout the spectrum of cancer initiation and progression has not been reported previously, and our work suggests that it will be instructive to characterize MBII dependence as a defining feature as these models are identified. The LF1/3T cells were incrementally transformed with TERT, LT and ST. We do not believe that MBII independence is mediated through the overexpression of TERT as HMECs immortalized with TERT have recently been shown to undergo transformation in an MBII-dependent manner (Cowling et al, 2007). Overexpression of the viral proteins LT and ST was employed to inactivate the tumor suppressors p53, pRb and PP2A .…”

“…MBI contains critical phosphorylation sites and is a region frequently mutated in Burkitt's Lymphomas (Bhatia et al, 1993;Bahram et al, 2000;Chang et al, 2000). The MBII region is essential for most biological functions, including transformation in all cell lines and mouse models reported (Stone et al, 1987;Oster et al, 2003;Herbst et al, 2005;Cowling et al, 2007). MBII is also a critical region for certain protein-protein interactions, including the interaction with an important co-factor in transformation, TRRAP (McMahon et al, 1998).…”

An N-Myc truncation analogous to c-Myc-S induces cell proliferation independently of transactivation but dependent on Myc homology box II

“…For example, Myc repression of several cell cycle inhibitors contributes to cell cycle progression, and Myc repression of the Wnt inhibitors, DKK1 and SFRP1 is necessary for epithelial cell transformation (Dang et al, 2006;Cowling and Cole, 2007a). The importance of Myc-dependent repression in cell proliferation was highlighted by the characterization of c-Myc-S, a truncated Myc protein translated from one of two closely spaced methionine codons, 102 or 111, in the full-length c-Myc coding mRNA (Spotts et al, 1997).…”