Tumour-suppressive role and clinical application of DAB2IP in triple-negative breast cancer

Dear Editor,

Breast cancer ranks the most frequent cancer type and the second most common cause of cancer-related death in women worldwide.¹ The breast cancer without estrogen receptor, progesterone receptor and HER2 expression determined by immunohistochemistry is referred to as triple-negative breast cancer (TNBC), which is found in about 20% of patients.² Compared to other tumour entities, the TNBC is characterized by higher metastatic probability and earlier disease relapse.³ Because of the insensitivity to targeted therapies (trastuzumab or pertuzumab) and endocrine therapies, the TNBC is treated with the standard chemotherapy.³ Once developed with metastatic disease, the overall survival of TNBC is only about 13–18 months.¹

In this issue of Clinical and Translational Medicine, Xiong et al. reported that DAB2 interacting protein (DAB2IP) inhibited TNBC tumourigenesis through a direct binding with small GTP-binding protein RAC1, which blocked the nuclear transportation of β-catenin and the transcription of its downstream targets. Downregulation of DAB2IP was associated with hypermethylation of DNA in TNBC patients, whereas the DNA demethylation drug, decitabine improved the sensitivity of patients to chemotherapy though DAB2IP. Accordingly, DAB2IP becomes a potential target for the treatment of TNBC with chemoresistance.

1 TUMOUR-SUPPRESSIVE ROLE OF DAB2IP

DAB2IP is also termed apoptosis signal-regulating kinase1-interacting protein-1 (AIP1), showing tumour-suppressive activity in a variety of tumours, such as prostate, ovarian and colorectal cancers.⁴ Being Ras-GTPase-activating proteins (GAP), DAB2IP prevents the Ras-dependent mitogenic signals during tumourigenesis.⁴ DAB2IP is also a scaffolding protein, which binds to key regulators of oncogenic signalling pathways in the control of multiple biological function in tumour cells. For instance, DAB2IP mediates the balance between cell survival and cell death cascades, such as the phosphatidylinositol 3-kinase (PI3K)-AKT signalling and the mitogen-activated protein (MAP)3K5-JNK signalling to maintain cellular homeostasis.⁵ Loss of DAB2IP not only enhances the survival signal but also results in the missegregation and aneuploid of chromosome, leading to chromosomal instability and chemoresistance of patients.⁶ Except for tumour growth, studies have also demonstrated the activity of DAB2IP in prevention of epithelial mesenchymal transition and tumour cell metastasis through the regulation of WNT/β-catenin and NF-κB signalling in prostate and colorectal cancers.^{4, 7} Given the multiple tumour-suppressive roles in a wide spectrum of tumours (Table 1), increase or reactivation of DAB2IP serves as important strategies for the improvement of patient's outcome. Notably, DAB2IP is seldom mutated but downregulated due to epigenetic silencing, posttranscriptional repression or proteasomal degradation during progression.⁴

2 TARGETING AT DNA METHYLATION IN CANCERS

Cancer cells accumulate both genetic and epigenetic mutations, whereas hypermethylation of CpG islands of tumour suppressors is frequently found during tumourigenesis.¹⁸ DNA methylation inhibitors have been considered the mainstay for the treatment of malignancies via the reactivation of respective tumour suppressors.¹⁸ DNA methyltransferase inhibitors (DNMTi) are a novel therapy against aberrant DNA methylation, which is routinely used for the treatment of myelodysplastic syndromes (MDS).¹⁸ The 5-Aza-2′-deoxycytidine (decitabine), which was approved for the treatment of MDS, shows therapeutic value for solid tumours.¹⁹ Xiong et al. demonstrated in their results that decitabine is efficient for TNBC via the upregulation of DAB2IP and restoration of its biological function against tumourigenesis. However, the DNMTi is also facing challenges nowadays. Insufficient TNF receptor–associated factor 6 expression in tumour lesion decreased the ubiquitination of the DNMT, leading to protein degradation and drug resistance.¹⁹

3 CANCER CELLS ADOPT STRATEGIES TO MAINTAIN STEMNESS

One characteristic of breast cancer cells is that they keep in dormant for decades from clinical diagnosis until recurrence.³ The dormant cells share similarities with stem cells, for example expression of stemness marker, self-renewal and tumour initiation.²⁰ They remain in the bone marrow and transform into cancer stem cells (CSCs) in suitable tissue microenvironments and become the source of metastatic cancer, leading to the poor prognosis of patients.²⁰ Other studies have deciphered the association of CSCs with drug resistance and immune evasion. During the gain of stemness, the Wnt/β-catenin signalling pathway plays an essential role via the nuclear transportation of β-catenin, activation of TCF transcriptional factor and upregulation of genes involved in cell stemness, for example c-MYC and Nanog.²¹ Nuclear enrichment of β-catenin is associated with cell self-renewal and resistance to sorafenib in liver cancer.²² Recently, a connection between DAB2IP and Wnt/β-catenin signalling has been detected, in which DAB2IP shows negative regulation on Wnt signalling and transcriptional factor c-Jun, which decreases the stemness of ovarian cancer.²³ In this issue, Xiong et al. identified that the downregulation of DAB2IP was responsible for the nuclear enrichment of β-catenin, activation of downstream targets (Nanog and Sox2) in the maintenance of TNBC stemness, thus providing a potential strategy to combat drug resistance for TNBC patients.

4 FUTURE PERSPECTIVES

Given TNBC the most challenging breast cancer subtype to treat, efforts can be made by the identification of novel molecular targets.¹ Two points with solid evidence support the importance of DAB2IP in the future treatment TNBC. First, DAB2IP expression is associated with TNBC patient's outcome, especially the drug response and drug sensitivity.^{5, 11} Accordingly, the level of DAB2IP protein can be evaluated and used as a biomarker for the predication of TNBC's prognosis. The second point is based on the multiple regulatory effects of DAB2IP on oncogenic signalling pathways enhanced by the impact of attenuated DAB2IP on cancer cell proliferation, metastasis and stemness, which supports DAB2IP as a potential target for drug development.⁴ Reestablishment of DAB2IP activity by DNA demethylation becomes an attractive strategy for the development of novel therapy against TNBC.

CONFLICTS OF INTEREST

The authors declare no conflicts of interest.