MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer.
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. MENAINVexpression 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 MENAINVconfer 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. ©2016 AACR.
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Madeleine J
MJ
Oudin
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.|ENS-Cachan, Cachan, France.
Lucie
L
Barbier
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Claudia
C
Schäfer
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Tatsiana
T
Kosciuk
Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.|Center for Systems Biology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
Miles A
MA
Miller
Lydia Hill Department for Bioinformatics, UT Southwestern Medical Center, Dallas, Texas.
Sangyoon
S
Han
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Oliver
O
Jonas
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.|Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Douglas A
DA
Lauffenburger
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts. fgertler@mit.edu.|Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Frank B
FB
Gertler
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005260:Female; D015870:Gene Expression; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics* / Q000378:metabolism; D008870:Microtubules / Q000378:metabolism; D009362:Neoplasm Metastasis; D017239:Paclitaxel / Q000494:pharmacology*; D020033:Protein Isoforms; D064726:Triple Negative Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
D000972:Antineoplastic Agents, Phytogenic; C511939:Enah protein, human; D008840:Microfilament Proteins; D020033:Protein Isoforms; D017239:Paclitaxel