Research Papers:

IQGAP1 control of centrosome function defines distinct variants of triple negative breast cancer

Mahasin A. Osman _, William James Antonisamy and Evgeny Yakirevich

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Oncotarget. 2020; 11:2493-2511. https://doi.org/10.18632/oncotarget.27623

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Mahasin A. Osman1,2, William James Antonisamy1 and Evgeny Yakirevich3

1 Department of Medicine, Division of Oncology, Health Sciences Campus, University of Toledo, Toledo, OH 43614, USA

2 Department of Molecular Pharmacology, Physiology and Biotechnology, Division of Biology and Medicine, Warren Alpert Medical School of Brown University, Providence, RI 02912, USA

3 Department of Pathology and Laboratory Medicine, Rhode Island Hospital, Warren Alpert Medical School of Brown University, Providence, RI 02903, USA

Correspondence to:

Mahasin A. Osman,email: [email protected],
[email protected]

Keywords: IQGAP1; BRCA1; β-catenin; MNK1; triple negative breast cancer

Received: March 27, 2020     Accepted: May 14, 2020     Published: June 30, 2020


Triple negative breast cancer (TNBC) is a heterogenous and lethal disease that lacks diagnostic markers and therapeutic targets; as such common targets are highly sought after. IQGAP1 is a signaling scaffold implicated in TNBC, but its mechanism is unknown. Here we show that IQGAP1 localizes to the centrosome, interacts with and influences the expression level and localization of key centrosome proteins like BRCA1 and thereby impacts centrosome number. Genetic mutant analyses suggest that phosphorylation cycling of IQGAP1 is important to its subcellular localization and centrosome-nuclear shuttling of BRCA1; dysfunction of this process defines two alternate mechanisms associated with cell proliferation. TNBC cell lines and patient tumor tissues differentially phenocopy these mechanisms supporting clinical existence of molecularly distinct variants of TNBC defined by IQGAP1 pathways. These variants are defined, at least in part, by differential mis-localization or stabilization of IQGAP1-BRCA1 and rewiring of a novel Erk1/2-MNK1-JNK-Akt-β-catenin signaling signature. We discuss a model in which IQGAP1 modulates centrosome-nuclear crosstalk to regulate cell division and imparts on cancer. These findings have implications on cancer racial disparities and can provide molecular tools for classification of TNBC, presenting IQGAP1 as a common target amenable to personalized medicine.

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