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Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence

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Review

Aberrant WNT/CTNNB1 Signaling as a Therapeutic Target in Human Breast Cancer: Weighing the Evidence

Emma H van Schie et al. Front Cell Dev Biol.

Abstract

WNT signaling is crucial for tissue morphogenesis during development in all multicellular animals. After birth, WNT/CTNNB1 responsive stem cells are responsible for tissue homeostasis in various organs and hyperactive WNT/CTNNB1 signaling is observed in many different human cancers. The first link between WNT signaling and breast cancer was established almost 40 years ago, when Wnt1 was identified as a proto-oncogene capable of driving mammary tumor formation in mice. Since that discovery, there has been a dedicated search for aberrant WNT signaling in human breast cancer. However, much debate and controversy persist regarding the importance of WNT signaling for the initiation, progression or maintenance of different breast cancer subtypes. As the first drugs designed to block functional WNT signaling have entered clinical trials, many questions about the role of aberrant WNT signaling in human breast cancer remain. Here, we discuss three major research gaps in this area. First, we still lack a basic understanding of the function of WNT signaling in normal human breast development and physiology. Second, the overall extent and precise effect of (epi)genetic changes affecting the WNT pathway in different breast cancer subtypes are still unknown. Which underlying molecular and cell biological mechanisms are disrupted as a result also awaits further scrutiny. Third, we survey the current status of targeted therapeutics that are aimed at interfering with the WNT pathway in breast cancer patients and highlight the importance and complexity of selecting the subset of patients that may benefit from treatment.

Keywords: beta-catenin; breast cancer; cancer stem cells; canonical Wnt signaling; mammary gland; non-canonical Wnt signaling; stem cells.

Figures

FIGURE 1
FIGURE 1
Detecting and targeting aberrant WNT signaling in human breast cancer. (A,B) Bubble plots illustrating the alteration of different WNT pathway components in breast versus colorectal cancer. Plots were generated using data from http://cbioportal.org (accessed on 20 September 2019), using the following datasets: Colorectal Adenocarcinoma (TCGA, Provisional), samples with mutation and copy number alteration data (220 patients/samples). Breast Invasive Carcinoma (TCGA, Provisional), samples with mutation and copy number alteration data (963 patients/samples). Circle sizes reflect the proportion of samples with alterations in each of the genes depicted, with the actual percentages shown. Note that copy number alterations (amplifications + deletions) and mutations (truncations + substitutions) were combined into a single score. No distinction was made between breast cancer subtypes. Data were not corrected for overall differences in mutation rates or genome instability between the different tumor types. No inference can be made about RNA and protein expression level changes based solely on these analyses. (A) APC is the most prominently mutated gene in colorectal cancer. Other endodermal cancers, including hepatocellular carcinoma, also show frequent genetic mutations in WNT/CTNNB1 signaling components (White et al., 2012). Depending on the tissue of origin and tumor subtype, activating mutations in CTNNB1 itself or inactivating mutations in negative regulators like APC or AXIN1 are more or less prevalent (Yanagisawa et al., 1992; Morin, 1997; Ishizaki et al., 2004). In breast cancer, genetic mutations in APC are rare. However, epigenetic changes such as APC promoter hypermethylation have been reported in the literature, with the highest incidence observed in inflammatory breast cancer (Jin et al., 2001; Van Der Auwera et al., 2008; Lindqvist et al., 2014). (B) The top genes that show genetic alterations in breast cancer are implicated to a lesser extent in colorectal cancer. Note that all of these components function at the level of ligand and receptor binding. The top two hits, RSPO2 and FZD6, have both been linked to reduced metastasis free survival, but likely operate via different WNT signaling mechanisms (Corda et al., 2017; Coussy et al., 2017). It should be stressed that in this respect, breast cancer is not unique. As more and more genome-wide expression profiling studies are becoming available, evidence is accumulating that many different cancers likely display changes in WNT/CTNNB1 signaling in the absence of mutations in APC or CTNNB1 (Wiese et al., 2018; Flanagan et al., 2019b). In addition, it was recently demonstrated that FZD7, which functions upstream of APC and CTNNB1, is required for WNT/CTNNB1 signaling in gastric tumors irrespective of their APC status (Flanagan et al., 2019a). This is reminiscent of earlier studies hinting toward a similar phenomenon for other upstream components (Suzuki et al., 2004). Even in colorectal cancer, the situation may thus be far more complex than envisioned, and the local niche may continue to affect signaling levels even when the WNT/CTNNB1 pathway is intrinsically activated through genetic mutations in APC (van Neerven and Vermeulen, 2019). (C) Cartoon showing the points of interception for WNT-pathway targeting drugs that are currently in clinical trials. See text for details.

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