PAK6 acts downstream of IQGAP3 to promote contractility in triple negative breast cancer cells.
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Embargo End Date
ICR Authors
Authors
Pipili, A
Babteen, NA
Kuwair, L
Jannet, MB
Quist, J
Ong, KKV
Pitaluga, R
Grigoriadis, AG
Tutt, A
Wells, CM
Babteen, NA
Kuwair, L
Jannet, MB
Quist, J
Ong, KKV
Pitaluga, R
Grigoriadis, AG
Tutt, A
Wells, CM
Document Type
Journal Article
Date
2024-09-01
Date Accepted
2024-05-16
Abstract
Breast cancer is a heterogeneous disease that remains the most common malignancy among women worldwide. During genomic analysis of breast tumours, mRNA levels of IQGAP3 were found to be upregulated in triple negative tumours. IQGAP3 was subsequently found to be expressed across a panel of triple negative breast cancer (TNBC) cell lines. Depleting expression levels of IQGAP3 delivered elongated cells, disrupted cell migration, and inhibited the ability of cells to form specialised invasive adhesion structures, termed invadopodia. The morphological changes induced by IQGAP3 depletion were found to be dependent on RhoA. Indeed, reduced expression of IQGAP3 disrupted RhoA activity and actomyosin contractility. Interestingly, IQGAP3 was also found to interact with p-21 activated kinase 6 (PAK6); a protein already associated with the regulation of cell morphology. Moreover, PAK6 depletion phenocopied IQGAP3 depletion in these cells. Whereas PAK6 overexpression rescued the IQGAP3 depletion phenotype. Our work points to an important PAK6-IQGAP3-RhoA pathway that drives the cellular contractility of breast cancer cells promoting both cell migration and adhesive invasion of these cells. As this phenotype is relevant to the process of metastasis and re-seeding of metastasis, the pharmacological targeting of PAK6 could lead to clinical benefit in TNBC patients.
Citation
Cellular Signalling, 2024, 121 pp. 111233 -
Source Title
Cellular Signalling
Publisher
ELSEVIER SCIENCE INC
ISSN
0898-6568
eISSN
1873-3913
Collections
Research Team
Directorate Breast Canc