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Targeting the Id1-Kif11 Axis in Triple-Negative Breast Cancer Using Combination Therapy

Abstract

The basic helix-loop-helix (bHLH) transcription factors inhibitor of differentiation 1 (Id1) and inhibitor of differentiation 3 (Id3) (referred to as Id) have an important role in maintaining the cancer stem cell (CSC) phenotype in the triple-negative breast cancer (TNBC) subtype. In this study, we aimed to understand the molecular mechanism underlying Id control of CSC phenotype and exploit it for therapeutic purposes. We used two different TNBC tumor models marked by either Id depletion or Id1 expression in order to identify Id targets using a combinatorial analysis of RNA sequencing and microarray data. Phenotypically, Id protein depletion leads to cell cycle arrest in the G0/G1 phase, which we demonstrate is reversible. In order to understand the molecular underpinning of Id proteins on the cell cycle phenotype, we carried out a large-scale small interfering RNA (siRNA) screen of 61 putative targets identified by using genomic analysis of two Id TNBC tumor models. Kinesin Family Member 11 (Kif11) and Aurora Kinase A (Aurka), which are critical cell cycle regulators, were further validated as Id targets. Interestingly, unlike in Id depletion conditions, Kif11 and Aurka knockdown leads to a G2/M arrest, suggesting a novel Id cell cycle mechanism, which we will explore in further studies. Therapeutic targeting of Kif11 to block the Id1-Kif11 axis was carried out using small molecular inhibitor ispinesib. We finally leveraged our findings to target the Id/Kif11 pathway using the small molecule inhibitor ispinesib in the Id+ CSC results combined with chemotherapy for better response in TNBC subtypes. This work opens up exciting new possibilities of targeting Id targets such as Kif11 in the TNBC subtype, which is currently refractory to chemotherapy. Targeting the Id1-Kif11 molecular pathway in the Id1+ CSCs in combination with chemotherapy and small molecular inhibitor results in more effective debulking of TNBC.

Type Journal
ISBN 2218-273X (Electronic) 2218-273X (Linking)
Authors Thankamony, A. P.; Murali, R.; Karthikeyan, N.; Varghese, B. A.; Teo, W. S.; McFarland, A.; Roden, D. L.; Holliday, H.; Konrad, C. V.; Cazet, A.; Dodson, E.; Yang, J.; Baker, L. A.; George, J. T.; Levine, H.; Jolly, M. K.; Swarbrick, A.; Nair, R.
Responsible Garvan Author A/Prof Alex Swarbrick
Publisher Name Biomolecules
Published Date 2020-09-08
Published Volume 10
Published Issue 9
Published Pages E1295
Status Always Electronic
DOI 10.3390/biom10091295
URL link to publisher's version https://www.ncbi.nlm.nih.gov/pubmed/32911668