Abstract
Constitutive Wnt signalling is characterized by excessive levels of β-catenin protein and is a frequent occurrence in cancer. APC and Axin are key components of the β-catenin destruction complex that acts to promote β-catenin degradation. The levels of Axin are in turn controlled by tankyrases, members of the PARP-family of poly-ADP-ribosylation enzymes. In colorectal cancer cells, which typically harbor APC mutations, inhibition of tankyrase activity promotes Axin stabilization and attenuates Wnt signalling. Here, we examined the effect of inhibiting tankyrases in breast cancer cells with normal APC. We show that application of the small molecule tankyrase inhibitor, XAV939 or siRNA-mediated abrogation of tankyrase expression increases Axin1 and Axin2 protein levels and attenuates Wnt-induced transcriptional responses in several breast cancer lines. In MDA-MB-231 cells, inhibiton of tankyrase activity also attenuate Wnt3a induced cell migration. Moreover, in both MDA-MB-231 and colorectal cancer cells, XAV939 inhibits cell growth under conditions of serum-deprivation. However, the presence of serum prevents this growth inhibitory effect, although inhibition of Wnt-induced transcriptional and migratory responses was maintained. These results indicate that stabilization of Axin by inhibition of tankyrases alone, may not be an effective means to block tumor cell growth and that combinatorial therapeutic approaches should be considered.
Highlights
Wnt signalling plays a fundamental role during development and in adult homeostasis and is inappropriately activated in many types of cancers [1,2,3]
Analysis of protein levels in aliquots of total cell lysates by immunoblotting revealed that Axin1 levels increased in MDA-MB-231 cells treated with XAV939 irrespective of the presence or absence of Wnt3a (Fig. 1A)
We examined the effect of tankyrase inhibitors in two other breast cancer cell lines, MCF-7 cells which are human epithelial-like cells of the Luminal A subtype that lack autocrine Wnt but are responsive to exogenous ligand [41,44,47] and EMT6 cells, a sarcoma-like mouse mammary breast cancer cell line, that has been utilized widely as a model system to study the effects of various treatments on local tumor growth and pulmonary metastasis [48,49,50]
Summary
Wnt signalling plays a fundamental role during development and in adult homeostasis and is inappropriately activated in many types of cancers [1,2,3]. Mutations and truncations in APC are linked to the familial adenomatous polyposis (FAP) coli syndrome and are found in the majority of sporadic colon carcinomas [8]. These alterations in APC or alternatively, mutations in b-catenin result in deregulation of b-catenin turnover and increase b-catenin/TCF signalling in colon cancer [1,2,3,9]. Mutations in APC or b-catenin are rare, but elevated levels of b-catenin are prevalent and this aberrant activity is thought to promote mammary carcinogenesis [10,11]. Wnt signalling plays an important role in stem cell-self renewal and may promote the growth of cancer stem cells, which are thought to drive tumorigenesis in a variety of solid tumors [10,13]
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