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MARCKS as a Potential Therapeutic Target in Inflammatory Breast Cancer.

Maroua Manai1,2,3, Ines ELBini-Dhouib4, Pascal Finetti5

  • 1Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY 10021, USA.

Cells
|September 23, 2022
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Summary

Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) is a potential therapeutic target for inflammatory breast cancer (IBC). Inhibiting MARCKS in IBC cells improved survival and mirrored molecular profiles, suggesting its role in IBC aggressiveness.

Keywords:
MARCKSMPS treatmentPTENinflammatory breast cancermechanismsmetastasis-free survival

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Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Inflammatory breast cancer (IBC) is highly metastatic, with Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein overexpression linked to poor survival.
  • MARCKS is associated with the PI3K/AKT pathway, and inhibitors are under development.

Purpose of the Study:

  • To investigate MARCKS as a therapeutic target in IBC, given its preferential expression in IBC compared to non-IBC (nIBC).
  • To evaluate the biologic activity of a MARCKS inhibitor (MPS) on IBC cell behavior and signaling pathways.
  • To assess the prognostic relevance of MARCKS and phosphatase and tensin homolog (PTEN) expression in IBC and nIBC patient samples.

Main Methods:

  • In vitro studies using IBC and nIBC cell lines treated with MPS to assess proliferation, migration, invasion, and mammosphere formation.
  • Analysis of PTEN/AKT and MAPK pathway protein expression changes in response to MPS treatment.
  • Immunohistochemistry (IHC) evaluation of MARCKS and PTEN expression in archival tumor samples from 180 IBC and 355 nIBC patients.

Main Results:

  • MPS treatment inhibited proliferation, migration, invasion, and mammosphere formation in IBC cells.
  • MARCKS inhibition upregulated PTEN and downregulated pAKT and pMAPK in IBC cells, but not nIBC cells.
  • MARCKS and PTEN expression were negatively correlated in IBC. MARCKS-/PTEN+ status correlated with longer metastasis-free survival (MFS) in IBC patients.

Conclusions:

  • MARCKS plays a functional role in IBC aggressiveness.
  • The MARCKS-/PTEN+ protein status, mirroring MPS-treated IBC cells, indicates a good prognosis in IBC patients.
  • MARCKS represents a potential therapeutic target for MARCKS-positive IBC, warranting further preclinical investigation.