8p22 MTUS1 Gene Product ATIP3 Is a Novel Anti-Mitotic Protein Underexpressed in Invasive Breast Carcinoma of Poor Prognosis

Abstract

BackgroundBreast cancer is a heterogeneous disease that is not totally eradicated by current therapies. The classification of breast tumors into distinct molecular subtypes by gene profiling and immunodetection of surrogate markers has proven useful for tumor prognosis and prediction of effective targeted treatments. The challenge now is to identify molecular biomarkers that may be of functional relevance for personalized therapy of breast tumors with poor outcome that do not respond to available treatments. The Mitochondrial Tumor Suppressor (MTUS1) gene is an interesting candidate whose expression is reduced in colon, pancreas, ovary and oral cancers. The present study investigates the expression and functional effects of MTUS1 gene products in breast cancer.Methods and FindingsBy means of gene array analysis, real-time RT-PCR and immunohistochemistry, we show here that MTUS1/ATIP3 is significantly down-regulated in a series of 151 infiltrating breast cancer carcinomas as compared to normal breast tissue. Low levels of ATIP3 correlate with high grade of the tumor and the occurrence of distant metastasis. ATIP3 levels are also significantly reduced in triple negative (ER- PR- HER2-) breast carcinomas, a subgroup of highly proliferative tumors with poor outcome and no available targeted therapy. Functional studies indicate that silencing ATIP3 expression by siRNA increases breast cancer cell proliferation. Conversely, restoring endogenous levels of ATIP3 expression leads to reduced cancer cell proliferation, clonogenicity, anchorage-independent growth, and reduces the incidence and size of xenografts grown in vivo. We provide evidence that ATIP3 associates with the microtubule cytoskeleton and localizes at the centrosomes, mitotic spindle and intercellular bridge during cell division. Accordingly, live cell imaging indicates that ATIP3 expression alters the progression of cell division by promoting prolonged metaphase, thereby leading to a reduced number of cells ungergoing active mitosis.ConclusionsOur results identify for the first time ATIP3 as a novel microtubule-associated protein whose expression is significantly reduced in highly proliferative breast carcinomas of poor clinical outcome. ATIP3 re-expression limits tumor cell proliferation in vitro and in vivo, suggesting that this protein may represent a novel useful biomarker and an interesting candidate for future targeted therapies of aggressive breast cancer.

8p deletion is strongly linked to poor prognosis in breast cancer

“…The fact that 8p deletions were markedly associated with rapid cell proliferation is potentially caused by deletion-dependent down-regulation of several wellknown cell-cycle control genes located at 8p21, 8p22 and 8p23, including for example LZTS1, an inhibitor of the Cdk1/cyclin B1 complex, 23 PINX1, which prolongs G0/S1 phase, 70 DLC1, an inducer of apoptosis, 71 and MTUS1, which delays progression of mitosis by prolonging metaphase. 21 Further steps for identification of putative tumor suppressor genes would include comparison between expression and copy numbers of 8p genes followed by functional studies. Such an analysis has been performed in liver cancer, suggesting that alterations of multiple genes might cooperatively drive tumor progression.…”

“…8p deletion typically involves extended areas or even the entire 8p arm, with several putative tumor suppressor genes which are located in this region. [17][18][19][20][21][22][23][24] Some breast cancer studies found associations between 8p deletions and advanced tumor stage, [25][26][27] highgrade, 28 metastatic growth, 25,27,29 familial breast cancer risk, 30 and poor prognosis, 25,27,29,31 but these associations could not be confirmed by others. 14,[32][33][34][35][36][37][38][39] To better understand the clinical relevance of 8p deletions in breast cancer, including association to tumor grade, pathological tumor stage, patient survival, hormone receptor status, and amplifications of HER2, MYC and CCND1, we analyzed more than 2,100 breast cancers with clinical follow-up data.…”

Gene Dysregulations Driven by Somatic Copy Number Aberrations-Biological and Clinical Implications in Colon Tumors

“…MTUS1 codes for a mitotic spindle-associated protein shown to be involved in the eventual reduction of mitotic rate. 75 Somatic copy number losses may also occur in narrower regions (may be as narrow as the gene locus) of the chromosomes. We have identified several cases with small deletions in a 10q region, which includes the PTEN locus.…”

ATIP, une nouvelle superfamille de protéines associées aux microtubules

“…Notre équipe a récemment mis en évidence une nouvelle protéine associée aux microtubules dénommée ATIP3 (AT2-interacting protein 3) [3], codée par le gène candidat suppresseur de tumeurs MTUS1 (microtubule-associated tumor suppressor ) 1 [4,5]. La molécule ATIP3 est localisée au centrosome et le long des microtubules dans les cellules en interphase.…”

“…En accord avec 1 Le gène MTUS1 a initialement été nommé mitochondrial tumor suppressor , sur la base des résultats de Seibold et al [11]. En 2010, lorsqu'il s'est avéré qu'ATIP3, ICIS et TIP150, produits des gènes MTUS1 et MTUS2, sont associés aux microtubules [3,7,8] …”