MALT1 protease as a mediator of chemotherapy resistance in triple-negative breast cancerBeecher, Maria Laura (2024) MALT1 protease as a mediator of chemotherapy resistance in triple-negative breast cancer. Doctoral Dissertation, University of Pittsburgh. (Unpublished)
AbstractBackground: Breast cancer is the most commonly diagnosed malignancy in American women. The triple-negative breast cancer (TNBC) subtype has among the worst prognosis due to high rates of recurrence and metastasis. Since TNBC lacks targetable receptor proteins, treatment relies upon non-specific chemotherapy, which can become ineffective upon onset of resistance. One potential driver of TNBC treatment resistance is MALT1 protease, the effector component of the CARMA-BCL10-MALT1 signaling complex, which induces pro-survival NF-ΚB transcriptional activity in multiple cancer cell types. Notably, it has been suggested that breast cancer cells demonstrate increased sensitivity to chemotherapies, doxorubicin and cisplatin, when MALT1 is depleted. Hence, we hypothesize that MALT1 protease is a pharmaceutically targetable driver of TNBC treatment resistance. Results/Conclusions: We found that MALT1 is highly expressed in basal breast cancer (a subtype largely composed of TNBC) and its expression in this context is associated with decreased response to anthracycline chemotherapies and reduced survival. MALT1 blockade, via siRNA knockdown or MALT1 protease inhibition increases doxorubicin sensitivity. Alternatively, overexpressing MALT1 leads to increased viability for doxorubicin-treated TNBC cells as compared to TNBC cells overexpressing empty vector or protease-deficient MALT1. These findings were confirmed in vivo by demonstrating that combination treatment of MALT1 protease inhibitor (JNJ-67856633) and doxorubicin resulted in significantly reduced tumor growth as compared to doxorubicin treatment alone. Mechanistically, we have shown for the first time that MALT1 protease is activated in response to treatment of TNBC cells with the DNA damaging agent, doxorubicin. We have found that MALT1 is not required for doxorubicin-induced NF-ΚB activation. Instead, our studies suggest a unique link between MALT1 and the DNA repair protein, ATM in which MALT1 protease activation in doxorubicin-treated cells partially depends on ATM. This may suggest a potential role for MALT1 in repair of doxorubicin-induced DNA damage. Altogether, our studies suggest that MALT1 inhibition may be a promising approach to improving chemotherapy response in TNBC. Share
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