Enhanced mitochondrial fission promotes chemosensitivity via SHP-1 activity in triple-negative breast cancer.

Elizabeth K Croom, Lillian E Walton, Alessandro J Bono, Anne Zhang, Brock A Humphries

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Article in Molecular biology reports, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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5 · Who and what money

Authors and funding

5 authors.

Elizabeth K CroomCenter for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.

Lillian E WaltonCenter for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.

Alessandro J BonoCenter for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.

Anne ZhangCenter for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA.

Brock A HumphriesCenter for Molecular Imaging, Department of Radiology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI, 48109, USA. brhu@med.umich.edu.

Funding

University of Michigan Department of Radiology Seed Grant U090365

6 · The paper itself

Abstract

backgroundTriple-negative breast cancer (TNBC) is an aggressive subtype with high chemoresistance and poor survival rates. While mitochondrial dynamics, fission and fusion, are implicated in chemoresistance, their precise roles remain largely unexplored. This study investigates how cytoplasmic phosphatases SHP-1 and SHP-2 regulate chemotherapeutic response in TNBC cells with altered mitochondrial dynamics.

methodsWe utilized click beetle green luciferase-expressing SUM149 and SUM159 TNBC cells engineered to stably express mitochondrial dynamics modulators (PISD, Drp1, MFN2). SHP-1/2 activity was further manipulated using either the inhibitor NSC87877 or stable shRNA knockdown, confirmed by qRT-PCR and Western Blotting. Cell growth and cytotoxicity were evaluated through bioluminescence imaging and drug assays using doxorubicin, paclitaxel, and salinomycin.

resultsWe show that SUM149 and SUM159 TNBC cells engineered to exhibit enhanced mitochondrial fission via increased PISD and Drp1 expression are more sensitive to doxorubicin and salinomycin, but not paclitaxel. SHP-1/2 inhibition attenuated doxorubicin and salinomycin sensitivity specifically in mitochondrial fission-enriched cells, with minimal effects in fusion-enriched cells and no effect on paclitaxel response. Notably, only SHP-1 knockdown reduced drug sensitivity in cells with enhanced mitochondrial fission, highlighting SHP-1 as a key regulator of chemoresistance. Conversely, enhanced mitochondrial fusion conferred resistance to cytotoxic agents.

conclusionsOur in vitro findings demonstrate that mitochondrial fission sensitizes TNBC cells to certain chemotherapeutics, and that SHP-1 critically regulates this response. This newly identified mechanism links mitochondrial dynamics to chemotherapeutic sensitivity, offering a potential pathway to overcome TNBC chemoresistance through targeted therapies.

Indexed as

Mitochondrial DynamicsProtein Tyrosine Phosphatase, Non-Receptor Type 6Triple Negative Breast NeoplasmsAntineoplastic AgentsCell Line, TumorCell ProliferationDoxorubicinDrug Resistance, NeoplasmFemaleHumansMitochondriaPaclitaxelPolyether PolyketidesPyransAntineoplastic AgentsDoxorubicinPaclitaxelPolyether PolyketidesProtein Tyrosine Phosphatase, Non-Receptor Type 6PTPN6 protein, humanPyranssalinomycinCell signalingDrug resistanceMitochondrial dynamicsSHP-1 (PTPN6)SHP-2 (PTPN11)Triple-negative breast cancer

Identifiers

PMID42640491

DOI10.1007/s11033-026-12615-y

PMCPMC13506572

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.