Targeting of MARK2, but not other MARKs, suppresses TNBC progression by inhibition of the mutant p53-driven signaling pathway

Abstract

Triple-negative breast cancer (TNBC) is the most challenging breast cancer subtype to treat due to the absence of effective targeted therapies. In this study, we demonstrate that elevated expression of microtubule affinity-regulating kinase 2 (MARK2), but not other MARK family members (MARK1, MARK3, and MARK4), correlates with poor prognosis in TNBC patients. Silencing MARK2 impairs TNBC progression via inhibition of mutant p53 (mutp53) signaling. In contrast, silencing any of the other three MARKs either enhances or does not affect TNBC cell growth or migration and has no impact on mutp53 expression. Notably, direct knockdown of mutp53 recapitulates the effects of MARK2 ablation in TNBC cells, further supporting a functional linkage. Moreover, ectopic expression of either wild-type (WT) MARK2 or its kinase-dead (KD) mutant enhances mutp53 signaling and promotes TNBC progression; however, MARK2 overexpression does not alter wild-type p53 (wtp53) expression or cell growth in luminal breast cancer cells. Significant inverse correlations are also observed between the expression levels of MARK2, THBS1, or HBEGF (two direct target genes of mutp53) and both overall and disease-free survival in TNBC patients harboring mutTP53, whereas no such association exists between MARK2 and survival in breast cancer subtypes expressing wtTP53. MARK2 is predominantly localized in the nucleus of TNBC cells, where it interacts with and stabilizes mutp53 through its UBA and Spacer domains. Consistent with this, MARK2-ΔUBA or MARK2-ΔSpacer mutant proteins fail to bind mutp53 or sustain its signaling, thereby acting as dominant-negative inhibitors that suppress TNBC progression. Collectively, our findings indicate that suppressing MARK2 expression, rather than inhibiting its kinase activity, may represent an effective therapeutic strategy for TNBC with mutTP53.

Keywords

MARK2 / mutp53 / THBS1 and HBEGF / Dominant-negative MARK2 / TNBC progression

Funding

This work was supported by the National Key Research and Development Program of China (No. 2023YFA1801900), the National Natural Science Foundation of China (Nos. 82125036, 82273964, and 82304538), the Jiangsu Provincial Natural Science Fund for Distinguished Young Scholar (No. BK20230042), and the Jiangsu Funding Program for Excellent Postdoctoral Talent(No. 2023ZB171).

Supporting information

Supplementary data associated with this article can be requested by sending E-mail to the corresponding authors.

Acknowledgements

We thank Prof. ZY Jiang (School of Pharmacy, China Pharmaceutical University) for designing and synthesizing the indicated compounds and PROTACs.

Declaration of competing interest

These authors declare no conflict of interest.

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