Format

Send to

Choose Destination
Mol Cancer Ther. 2017 Jan;16(1):143-155. doi: 10.1158/1535-7163.MCT-16-0413. Epub 2016 Nov 3.

MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.

Author information

1
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
2
ENS-Cachan, Cachan, France.
3
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
4
Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
5
Lydia Hill Department for Bioinformatics, UT Southwestern Medical Center, Dallas, Texas.
6
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. fgertler@mit.edu.
7
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.

Abstract

Taxane therapy remains the standard of care for triple-negative breast cancer. However, high frequencies of recurrence and progression in treated patients indicate that metastatic breast cancer cells can acquire resistance to this drug. The actin regulatory protein MENA and particularly its invasive isoform, MENAINV, are established drivers of metastasis. MENAINV expression is significantly correlated with metastasis and poor outcome in human patients with breast cancer. We investigated whether MENA isoforms might play a role in driving resistance to chemotherapeutics. We find that both MENA and MENAINV confer resistance to the taxane paclitaxel, but not to the widely used DNA-damaging agents doxorubicin or cisplatin. Furthermore, paclitaxel treatment does not attenuate growth of MENAINV-driven metastatic lesions. Mechanistically, MENA isoform expression alters the ratio of dynamic and stable microtubule populations in paclitaxel-treated cells. MENA expression also increases MAPK signaling in response to paclitaxel treatment. Decreasing ERK phosphorylation by co-treatment with MEK inhibitor restored paclitaxel sensitivity by driving microtubule stabilization in MENA isoform-expressing cells. Our results reveal a novel mechanism of taxane resistance in highly metastatic breast cancer cells and identify a combination therapy to overcome such resistance. Mol Cancer Ther; 16(1); 143-55.

PMID:
27811011
PMCID:
PMC5359014
DOI:
10.1158/1535-7163.MCT-16-0413
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center