MASTL overexpression promotes chromosome instability and metastasis in breast cancer

Abstract

MASTL kinase is essential for correct progression through mitosis, with loss of MASTL causing chromosome segregation errors, mitotic collapse and failure of cytokinesis. However, in cancer MASTL is most commonly amplified and overexpressed. This correlates with increased chromosome instability in breast cancer and poor patient survival in breast, ovarian and lung cancer. Global phosphoproteomic analysis of immortalised breast MCF10A cells engineered to overexpressed MASTL revealed disruption to desmosomes, actin cytoskeleton, PI3K/AKT/mTOR and p38 stress kinase signalling pathways. Notably, these pathways were also disrupted in patient samples that overexpress MASTL. In MCF10A cells, these alterations corresponded with a loss of contact inhibition and partial epithelial–mesenchymal transition, which disrupted migration and allowed cells to proliferate uncontrollably in 3D culture. Furthermore, MASTL overexpression increased aberrant mitotic divisions resulting in increased micronuclei formation. Mathematical modelling indicated that this delay was due to continued inhibition of PP2A-B55, which delayed timely mitotic exit. This corresponded with an increase in DNA damage and delayed transit through interphase. There were no significant alterations to replication kinetics upon MASTL overexpression, however, inhibition of p38 kinase rescued the interphase delay, suggesting the delay was a G2 DNA damage checkpoint response. Importantly, knockdown of MASTL, reduced cell proliferation, prevented invasion and metastasis of MDA-MB-231 breast cancer cells both in vitro and in vivo, indicating the potential of future therapies that target MASTL. Taken together, these results suggest that MASTL overexpression contributes to chromosome instability and metastasis, thereby decreasing breast cancer patient survival.

Chromosomal Instability in Tumor Initiation and Development

“…Chromosome segregation errors can promote the number of micronuclei that when ruptured, cause enhanced cytosolic DNA, activate downstream noncanonical NF-kB signaling, and activate the cytosolic DNA-sensing cGAS-STING pathway in CIN-high breast cancer cells, hence stimulating cancer metastases (69). The amplification and overexpression of MASTL, an essential kinase for correct progression through mitosis, correlates with enhanced CIN in breast cancer and poor patient survival, whereas knockdown of MASTL may suppress breast cancer metastasis in vivo (70). CIN has also been suggested to initiate the formation of somatic copy-number alterations (SCNA; ref.…”

MASTL: A novel therapeutic target for Cancer Malignancy

“…Furthermore, increased MASTL expression has been associated with poor outcomes in breast, oral, gastric, colon, and head and neck cancer, suggesting that MASTL plays a master role in carcinogenesis. [24][25][26]49,[52][53][54] Disrupting the MASTL-ENSA-PP2A-B55 (MEP) axis results in multiple mitotic errors 21,50,55,56 which then drive CIN, a hallmark of cancer. 57 Recent studies have also demonstrated that MASTL promotes oncogenesis and therapy resistance in cancer cells by enhancing oncogenic AKT kinase activity 54 and Wnt signaling.…”

“…24,52,53,58 Similar studies in breast cancer have demonstrated that MASTL expression correlates significantly with increased CIN, mitotic index, histological grade, poor overall survival and with a high risk of metastatic relapse in estrogen receptor (ER) positive patients. 25,49,52,59 Overexpression of wild-type MASTL in immortalized human MCF10A breast epithelial cells was sufficient to increase the rate of chromosome bridges, micronuclei formation as well as to induce loss of contact inhibition, 25,54 whereas inhibition of MASTL selectively killed breast cancer cells by induction of mitotic catastrophe. 52 Other than its effects on mitosis, MASTL promotes oncogenesis by activating AKT kinase activity via degradation of its phosphatase, PH (pleckstrin homology) domain Leucine-rich repeat Protein Phosphatase (PHLPP), 54 regulates normal DNA replication timing 60 and recovery from the premitotic DNA damage checkpoint arrest.…”

“…61 Overall, upregulation of MASTL expression induces partial epithelial to mesenchymal transition (EMT), abnormal proliferation growth, as well as disrupts the timing of mitotic exit, increased chromosome segregation defects and micronuclei formation. 25,26 In 42.9% of gastric cancer patients, MASTL was significantly associated with cancer metastasis, tumor relapse, and poor overall survival, suggesting the potential of MASTL expression as a valuable prognostic marker and a potential therapeutic target for patients with gastric cancer. 26 Similarly, Cetti et al identified MASTL as an important target for thyroid tumor cells.…”

“…[17][18][19][20] The role of MASTL in regulating mitosis is now well-defined. [20][21][22] Also, a key role of MASTL in oncogenesis has recently been proposed in different cancer types, [23][24][25][26] however, details of the underlying mechanism/s and/or factors regulating MASTL expression/ activity during cancer progression remain unclear and needs detailed molecular investigation. In the light of the critical role of MASTL in cancer progression and unclear knowledge of its cancer promoting role and regulation, we present this review article that summarizes the knowledge from the recent publications regarding the role of MASTL deregulation in cancer progression, mechanism/s by which MASTL promotes tumorigenesis and its efficacy as a novel anticancer therapeutic target.…”