Abstract
Triple-negative breast cancer (TNBC) shows limited therapeutic efficacy. PARP inhibitor has been approved to treat advanced BRCA-mutant breast cancer but shows high resistance. Therefore, the development of new therapeutics that sensitize TNBC irrespective of BRCA status is urgently needed. The neddylation pathway plays a critical role in many physiological processes by regulating the degradation of proteins. MLN4924, a selective inhibitor of the key neddylation enzyme NEDD8 Activation Enzyme (NAE1), shows higher sensitivity to both BRCA1-wild type and -mutant TNBCs compared to other breast cancer subtypes. MLN4924 induced re-replication with >4N DNA content leading to robust DNA damage. Accumulation of unrepaired DNA damage resulted in S and G2/M arrest causing apoptosis and senescence, due to the stabilization of the replication initiation protein CDT1 and the accumulation of cell cycle proteins upon MLN4924 treatment. Moreover, adding MLN4924 to the standard TNBC chemotherapeutic agent cisplatin increased the DNA damage level, further enhancing the sensitivity. In vivo, MLN4924 reduced tumor growth in a NOD-SCID mouse xenograft model by inducing DNA damage which was further augmented with the MLN4924 and cisplatin cotreatment. NAE1 is overexpressed in TNBC cell lines and in patients compared to other breast cancer subtypes suggesting that NAE1 status is prognostic of MLN4924 treatment response and outcome. Taken together, we demonstrated the mechanism of TNBC sensitization by the MLN4924 and MLN4924/cisplatin treatments irrespective of BRCA1 status, provided a strong justification for using MLN4924 alone or in combination with cisplatin, and identified a genetic background in which this combination will be particularly effective.
Highlights
Triple-negative breast cancer (TNBC) comprises 15–20% of breast cancer
Given that MLN4924 is a specific inhibitor of NAE1, we evaluated the expression of the neddylation enzymes by Western blot (WB) assay in TNBC and nonTNBC cell lines and found that NAE1 is overexpressed in the TNBC group compared to the non-TNBC group (p < 0.01) while UBA3, UBE2M, and NEDD8 did not show significant differences between these two groups (p > 0.05) (Figure 1C)
Analyses of a publicly available breast cancer patient gene expression database confirmed that NAE1 is overexpressed in TNBC patient samples compared to non-TNBC samples (p < 0.0001) while UBA3, UBE2M, and NEDD8 expression did not show a significant difference (p > 0.05) (Figure 2A–2D)
Summary
Triple-negative breast cancer (TNBC) comprises 15–20% of breast cancer. This breast cancer subtype does not express estrogen alpha receptors (ER) or progesterone receptors (PR) and lacks overexpression of the HER2 gene [1]. (adenosine diphosphate (ADP)-ribose) polymerase inhibitor (PARPi) has been approved to treat metastatic BRCA-mutant breast cancer [2, 3]. BRCA1 and BRCA2 are involved in DNA damage repair by homologous recombination (HR), replication fork stabilization, and maintenance of genomic stability [4, 5]. Mutations in these genes predispose patients to hereditary breast cancer [5]
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