Role and Involvement of TENM4 and miR-708 in Breast Cancer Development and Therapy

Abstract

Teneurin 4 (TENM4) is a transmembrane protein that is codified by the ODZ4 gene and is involved in nervous system development, neurite outgrowth, and neuronal differentiation. In line with its involvement in the nervous system, TENM4 has also been implicated in several mental disorders such as bipolar disorder, schizophrenia, and autism. TENM4 mutations and rearrangements have recently been identified in a number of tumors. This, combined with impaired expression in tumors, suggests that it may potentially be involved in tumorigenesis. Most of the TENM4 mutations that are observed in tumors occur in breast cancer, in which TENM4 plays a role in cells’ migration and stemness. However, the functional role that TENM4 plays in breast cancer still needs to be better evaluated, and further studies are required to better understand the involvement of TENM4 in breast cancer progression. Herein, we review the currently available data for TENM4′s role in breast cancer and propose its use as both a novel target with which to ameliorate patient prognosis and as a potential biomarker. Moreover, we also report data on the tumorigenic role of miR-708 deregulation and the possible use of this miRNA as a novel therapeutic molecule, as miR-708 is spliced out from TENM4 mRNA.

Examples of Inverse Comorbidity between Cancer and Neurodegenerative Diseases: A Possible Role for Noncoding RNA

“…The biological functions of miRNAs are only partially understood; certainly, miRNAs play crucial roles in cell proliferation, cell death, developmental stages of organisms, stress resistance and various aspects of metabolism [ 115 ]. Moreover, there are several indications that miRNAs might be involved in human tumorigenesis [ 116 , 117 , 118 , 119 ]. In this review, we want to emphasize the role of miR-519a-3p in both oncological and neurodegenerative processes.…”

The Double Face of miR-708: A Pan-Cancer Player with Dissociative Identity Disorder

“…In humans, miR-708 is a mirtron (together with miR-5579) generated through the splicing of intron 1 of the ODZ4 gene [ 13 , 14 ], thus its processing after transcription by RNApol II does not involve Drosha ( Figure 1 A). ODZ4 (located on 11q14.1) encodes the Teneurin Transmembrane Protein 4 (TENM4), a highly conserved glycosylated type II transmembrane protein with important roles during the development of the nervous system and neuronal differentiation [ 15 ]. TENM4 dysregulation has been inversely associated with relapse-free survival in breast carcinomas [ 15 , 16 ].…”

“…ODZ4 (located on 11q14.1) encodes the Teneurin Transmembrane Protein 4 (TENM4), a highly conserved glycosylated type II transmembrane protein with important roles during the development of the nervous system and neuronal differentiation [ 15 ]. TENM4 dysregulation has been inversely associated with relapse-free survival in breast carcinomas [ 15 , 16 ]. Alternatively, ovarian tumors with lower levels of this protein showed less differentiated, and more aggressive, phenotypes [ 17 ].…”

Ten‐m4 plays a unique role in the establishment of binocular visual circuits

“…Ten‐m4 has been identified with a range of functions including oligodendrocyte differentiation (Suzuki et al., 2012), muscle cell regeneration (Yamaguchi et al., 2012), astrocyte morphology (Takano et al., 2020), and tumorigenesis (Peppino et al., 2022). Mutations of Ten‐m4 have been found to be associated with Parkinson's disease (Pu et al., 2020), essential tremor (Hor et al., 2015), autism spectrum disorder (Iossifov et al., 2014), schizophrenia (Xue et al., 2018; Yi et al., 2021), and bipolar disorder (Ikeda et al., 2018; Sklar et al., 2011) although its role is not clear.…”