Yoon Pin Lim

Metformin is an antidiabetic drug that has been tested widely as an anti-cancer agent. However, data from clinical trials have been mixed. Evidence for metformin’s efficacy in HER2+ breast cancer exists. Hence, we evaluated whether WBP2, a HER2-coamplified gene, can regulate the response of HER2+ breast cancer to metformin. Identification of biomarkers for predicting metformin response has implications in repurposing metformin for precision oncology. The effect of WBP2 on breast cancer response to metformin was studied using in vitro and mouse models. The mechanism of WBP2 on metformin-induced AMPK activation was elucidated, and its co-expression with p-AMPK was examined in clinical specimens using IHC. RNA-seq analyses were performed to elucidate WBP2’s mechanism in energy metabolism. WBP2 inhibited the metformin response of HER2+ breast cancer in vitro and in vivo. These effects were concomitant with WBP2-mediated repression of metformin-induced AMPK activation and mTOR inhibition in HER2+ breast cancer cells, a lower AMP:ATP ratio state, and enhanced glycolytic capacity and mitochondria respiration. Analysis of HER2-positive breast cancer samples supports the negative correlation between WBP2 expression and activated AMPK observed in vitro. RNA-seq analysis revealed the potential mechanism of WBP2 in regulating ATP production processes and preferential effect of WBP2 on metformin response in HER2+ breast cancer. This study reported a novel role of WBP2 in cancer metabolism and energetics that contributes new insights into the molecular etiology of cancer. WBP2 may be a biomarker for patient stratification, paving the way towards repurposing metformin for precision oncology.

Dysregulation of transcription coregulators is common in cancers, supporting the key role for this group of proteins in cancer development. WW domain‐binding protein 2 (WBP2) transcription coactivator is an emerging oncogene, first discovered in breast cancer and increasingly implicated in other human cancers except sex‐related cancers. Here, we review the latest findings on the roles of WBP2 in human cancers and explore its function and network of transcriptional coregulators in ovarian and prostate cancers. Through the creation of a protein‐interaction map of the sex hormone receptor coregulators, biologically meaningful observations and testable hypotheses were generated. Coupling the protein‐interaction map with information from published literature reveals that the WBP2 transcription coactivator might play a role in ovarian and prostate cancers via protein complexes comprising Hippo pathway signaling components YAP and TAZ, Wnt pathway‐related β‐Catenin, and sex hormone receptor coregulators such as CBP/P300, NCOA3, and PGC‐1α. Meta‐analysis of public databases also revealed aberrant levels of these proteins in ovarian and prostate cancer, and found WBP2 overexpression in the immunoreactive ovarian cancer subtype, further supporting the role of these specific protein complexes in ovarian cancer. Finally, we reviewed the challenges in chemo and hormonal therapy and posit that WBP2‐positive ovarian and prostate cancer might benefit from combinational therapy involving hormonal and immunotherapy.

Cancer is a global health problem. The delineation of molecular mechanisms pertinent to cancer initiation and development has spurred cancer therapy in the form of precision medicine. The Hippo signalling pathway is a tumour suppressor pathway implicated in a multitude of cancers. Elucidation of the Hippo pathway has revealed an increasing number of regulators that are implicated, some being potential therapeutic targets for cancer interventions. WW domain-binding protein 2 (WBP2) is an oncogenic transcriptional co-factor that interacts, amongst others, with two other transcriptional co-activators, YAP and TAZ, in the Hippo pathway. WBP2 was recently discovered to modulate the upstream Hippo signalling components by associating with LATS2 and WWC3. Exacerbating the complexity of the WBP2/Hippo network, WBP2 itself is reciprocally regulated by Hippo-mediated microRNA biogenesis, contributing to a positive feedback loop that further drives carcinogenesis. Here, we summarise the biological mechanisms of WBP2/Hippo reciprocal regulation and propose therapeutic strategies to overcome Hippo defects in cancers through targeting WBP2.

WW‐domain‐binding protein 2 ( WBP2 ) is an oncogene that drives breast carcinogenesis through regulating Wnt, estrogen receptor (ER), and Hippo signaling. Recent studies have identified neoteric modes of action of WBP2 other than its widely recognized function as a transcriptional coactivator. Here, we identified a previously unexplored role of WBP2 in inflammatory signaling in breast cancer via an integrated proteogenomic analysis of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA BRCA) dataset. WBP2 was shown to enhance the migration and invasion in triple‐negative breast cancer (TNBC) cells especially under tumor necrosis factor alpha (TNF‐α) stimulation. Molecularly, WBP2 potentiates TNF‐α‐induced nuclear factor kappa B (NF‐κB) transcriptional activity and nuclear localization through aggrandizing ubiquitin‐mediated proteasomal degradation of its upstream inhibitor, NF‐κB inhibitor alpha (NFKBIA; also known as IκBα). We further demonstrate that WBP2 induces mRNA stability of beta‐transducin repeat‐containing E3 ubiquitin protein ligase ( BTRC ), which targets IκBα for ubiquitination and degradation. Disruption of IκBα rescued the impaired migratory and invasive phenotypes in WBP2 ‐silenced cells, while loss of BTRC ameliorated WBP2‐driven migration and invasion. Clinically, the WBP2‐BTRC‐IκBα signaling axis correlates with poorer prognosis in breast cancer patients. Our findings reveal a pivotal mechanism of WBP2 in modulating BTRC‐IκBα‐NF‐κB pathway to promote TNBC aggressiveness.

WBP2 is an emerging oncoprotein with diverse functions in breast tumorigenesis via regulating Wnt, epidermal growth factor receptor, estrogen receptor, and Hippo. Recently, evidence shows that WBP2 is tightly regulated by the components of the miRNA biogenesis machinery such as DGCR8 and Dicer via producing both WBP2’s 3′UTR and coding DNA sequence-targeting miRNAs. This led us to hypothesize that WBP2 could provide a feedback loop to the biogenesis of its key upstream regulators by regulating the microprocessor complex activity. Indeed, WBP2 suppressed microprocessor activity by blocking the processing of pri-miRNAs to pre-miRNAs. WBP2 negatively regulated the assembly of the microprocessor complex via physical interactions with its components. Meta-analyses suggest that microprocessor complex components, in particular DGCR8, DDX5, and DEAD-Box Helicase17 (DDX17), have tumor-suppressive properties. 2D and 3D in vitro proliferation assays revealed that WBP2 blocked the tumor-suppressive properties of DGCR8, a key component of the microprocessor complex. In conclusion, WBP2 is a novel regulator of miRNA biogenesis that is a known dysregulated pathway in breast tumorigenesis. The reregulation of miRNA biogenesis machinery via targeting WBP2 protein may have implications in breast cancer therapy.

Dysregulation of signaling pathways is responsible for many human diseases. The lack of understanding of the molecular etiology of gastric cancer (GC) poses a substantial challenge to the development of effective cancer therapy. To better understand the molecular mechanisms underlying the pathogenesis of GC, which will facilitate the identification and development of effective therapeutic approaches to improve patient outcomes, mass spectrometry‐based phosphoproteomics analysis was performed to map the global molecular changes in GC. A total of 530 proteins with altered phosphorylation levels were detected across a panel of 15 normal and GC cell lines. WW domain‐binding protein 2 (WBP2) was validated to be upregulated in a subset of GC cell lines. WBP2 is overexpressed in 61% cases of GC compared to non‐cancer tissues and high WBP2 expression correlates with poor clinical outcomes. WBP2 was found to be required for GC cell migration but is dispensable for cell growth and proliferation. WBP2 knockdown increased p‐LATS2 with a concomitant increase in p‐YAP, resulting in the cytoplasmic retention of YAP and ultimately the inhibition of YAP/TEAD activity and downregulation of TEAD target genes–– CTGF and CYR61 . Importantly, the loss of LATS2 reversed the activation of Hippo pathway caused by WBP2 knockdown, indicating that WBP2 acts through LATS2 to exert its function on the Hippo pathway. Moreover, WBP2 interacted with LATS2 to inhibit its phosphorylation and activity. In conclusion, our study established a pivotal role for WBP2 in the promotion of GC cell migration via a novel mechanism that inactivates the Hippo pathway transducer LATS2.

WBP2 transcription coactivator is an emerging oncoprotein and a key node of convergence between EGF and Wnt signaling pathways. Understanding how WBP2 is regulated has important implications for cancer therapy. WBP2 is tightly controlled by post-translational modifications, including phosphorylation and ubiquitination, leading to changes in subcellular localization, protein–protein interactions, and protein turnover. As the function of WBP2 is intricately linked to YAP and TAZ, we hypothesize that WBP2 is negatively regulated by the Hippo tumor suppressor pathway. Indeed, MST is demonstrated to negatively regulate WBP2 expression in a kinase-dependent but LATS-independent manner. This was observed in the majority of the breast cancer cell lines tested. The effect of MST was enhanced by SAV and concomitant with the inhibition of the transcription co-activation, in vitro and in vivo tumorigenesis activities of WBP2, resulting in good prognosis in xenografts. Downregulation of WBP2 by MST involved miRNA but not proteasomal or lysosomal degradation. Our data support the existence of a novel MST-Dicer signaling axis, which in turn regulates both WBP2 CDS- and UTR-targeting miRNAs expression, including miR-23a. MiR-23a targets the 3′UTR of WBP2 mRNA directly. Significant inverse relationships between WBP2 and MST or miR23a expression levels in clinical specimens were observed. In conclusion, WBP2 is a target of the Hippo/MST kinase; MST is identified as yet another rheostat in the regulation of WBP2 and its oncogenic function. The findings have implications in targeted therapeutics and precision medicine for breast cancer.

WW domain-binding protein 2 (WBP2) is an emerging oncoprotein. Over the past decade, WBP2 surfaced as a key node connecting key signaling pathways associated with ER/PR, EGFR, PI₃K, Hippo, and Wnt in cancer. In addition to the oncogenic functions of WBP2, this review discusses the latest research regarding the multilevel regulation and modes of action of WBP2 and how they can be exploited for molecular medicine. In translational research, evidence supports the role of WBP2 as a biomarker for early detection, prognosis, and companion diagnostics in breast cancer. Finally, we envision new trends in WBP2 research in the space of molecular etiology of cancer, targeted therapeutics, and precision medicine.

Purpose: Trastuzumab-based chemotherapy has shown remarkable clinical benefits for HER2-positive breast cancer patients. However, treatment regimens involving trastuzumab had little or no effect for a subset of patients. Preliminary studies revealed WW-binding protein 2 (WBP2), an oncogenic transcription co-activator, to be co-amplified with HER2 in 36% of HER2-positive breast cancers. We hypothesize that WBP2 regulates and correlates with the response of HER2-positive breast cancer to trastuzumab. Experimental Design: The co-expression of WBP2 and HER2 in breast tumors was validated using immunohistochemistry. The role and mechanism of WBP2 in regulating breast cancer response to trastuzumab was elucidated using in vitro, patient-derived xenograft and murine xenograft models. A multi-center retrospective study involving 143 patients given neoadjuvant trastuzumab-based chemotherapy was conducted to determine if WBP2 expression correlates with pathologic complete response. Results: Elevated expression of WBP2 significantly enhanced breast cancer's response to trastuzumab by augmenting trastuzumab-induced downregulation of HER2 and arrest of cell cycle via inhibition of cyclin D expression. High level of WBP2 correlated with better pathologic complete response (67.19%) compared to low WBP2 level (26.58%). The highest response was observed in subgroups of patients with high WBP2-expressing tumors and also aged below 50 years (77.78%) or were pre-menopausal in status (73.33%). Retrospectively, WBP2 demonstrated sensitivity of 80 to 81% and specificity of 76.5 to 80% in discriminating between patients showing pCR and non-pCR. Conclusions: WBP2 expression correlates with the response of HER2-positive breast cancer to trastuzumab-based neoadjuvant chemotherapy.