8p22 MTUS1 gene product ATIP3 is a novel anti-mitotic protein underexpressed in invasive breast carcinoma of poor prognosis.
BACKGROUND
Breast 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.


RESULTS
By 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.


CONCLUSIONS
Our 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.
Institut Cochin, Université Paris Descartes, Inserm U567, CNRS UMR8104, Paris, France.
Sylvie
S
Rodrigues-Ferreira
Anne
A
Di Tommaso
Ariane
A
Dimitrov
Sylvie
S
Cazaubon
Nadège
N
Gruel
Hélène
H
Colasson
André
A
Nicolas
Nathalie
N
Chaverot
Vincent
V
Molinié
Fabien
F
Reyal
Brigitte
B
Sigal-Zafrani
Benoit
B
Terris
Olivier
O
Delattre
François
F
Radvanyi
Franck
F
Perez
Anne
A
Vincent-Salomon
Clara
C
Nahmias
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics*; D002277:Carcinoma / Q000235:genetics*; D002352:Carrier Proteins / Q000096:biosynthesis* / Q000235:genetics; D049109:Cell Proliferation; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000648:ultrastructure*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D008938:Mitosis; D009361:Neoplasm Invasiveness; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis* / Q000235:genetics
D002352:Carrier Proteins; C474762:MTUS1 protein, human; C488664:Mtus1 protein, mouse; D025521:Tumor Suppressor Proteins