MENA Confers Resistance to Paclitaxel in Triple-Negative Breast Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metastasis

Background:

• Triple-negative breast cancer (TNBC) treatment relies on taxane chemotherapy.
• High rates of recurrence and progression indicate acquired taxane resistance.
• The MENA protein, particularly its invasive isoform (MENA^INV), drives metastasis and is linked to poor patient outcomes.

Purpose of the Study:

• To investigate the role of MENA isoforms in mediating resistance to chemotherapeutics in breast cancer.
• To elucidate the mechanisms by which MENA isoforms confer taxane resistance.
• To identify potential therapeutic strategies to overcome MENA-mediated taxane resistance.

Main Methods:

• Assessed the effect of MENA and MENA^INV expression on cellular response to paclitaxel, doxorubicin, and cisplatin.
• Investigated the impact of paclitaxel treatment on MENA^INV-driven metastatic lesions.
• Analyzed changes in microtubule dynamics and MAPK signaling pathways in response to MENA expression and paclitaxel treatment.
• Evaluated the efficacy of combining MEK inhibitors with paclitaxel to restore sensitivity.

Main Results:

• Both MENA and MENA^INV conferred resistance to paclitaxel but not to doxorubicin or cisplatin.
• Paclitaxel treatment did not inhibit the growth of MENA^INV-driven metastatic lesions.
• MENA isoforms altered microtubule stability and increased MAPK signaling (ERK phosphorylation) upon paclitaxel exposure.
• Co-treatment with a MEK inhibitor restored paclitaxel sensitivity by promoting microtubule stabilization.

Conclusions:

• MENA isoforms represent a novel mechanism of taxane resistance in highly metastatic breast cancer.
• MENA-driven resistance involves altered microtubule dynamics and enhanced MAPK signaling.
• Combination therapy with MEK inhibitors and taxanes offers a promising strategy to overcome resistance in breast cancer.