MARCKS as a Potential Therapeutic Target in Inflammatory Breast Cancer

Maroua Manai; Ines ELBini-Dhouib; Pascal Finetti; Haifa Bichiou; Carolina Reduzzi; Dorra Aissaoui; Naziha Ben-Hamida; Emilie Agavnian; Najet Srairi-Abid; Marc Lopez; Fatma Amri; Lamia Guizani-Tabbane; Khaled Rahal; Karima Mrad; Mohamed Manai; Daniel Birnbaum; Emilie Mamessier; Massimo Cristofanilli; Hamouda Boussen; Maher Kharrat; Raoudha Doghri; François Bertucci

doi:10.3390/cells11182926

MARCKS as a Potential Therapeutic Target in Inflammatory Breast Cancer

Cells. 2022 Sep 19;11(18):2926. doi: 10.3390/cells11182926.

Authors

Maroua Manai^{1

2

3}, Ines ELBini-Dhouib⁴, Pascal Finetti⁵, Haifa Bichiou⁶, Carolina Reduzzi¹, Dorra Aissaoui⁴, Naziha Ben-Hamida³, Emilie Agavnian⁷, Najet Srairi-Abid⁴, Marc Lopez⁵, Fatma Amri⁸, Lamia Guizani-Tabbane⁶, Khaled Rahal⁹, Karima Mrad³, Mohamed Manai¹⁰, Daniel Birnbaum⁵, Emilie Mamessier⁵, Massimo Cristofanilli¹, Hamouda Boussen¹¹, Maher Kharrat², Raoudha Doghri³, François Bertucci^{5

12

13}

Affiliations

¹ Department of Medicine, Division of Hematology-Oncology, Weill Cornell Medicine, New York, NY 10021, USA.
² Human Genetics Laboratory (LR99ES10), Faculty of Medicine of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia.
³ Anatomic Pathology Department, Salah Azaiz Institute, Tunis 1006, Tunisia.
⁴ Biomolecules Laboratory of Venins and Theranostic Applications, Pasteur Institute of Tunis, Tunis 1002, Tunisia.
⁵ Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, Aix-Marseille University, «Equipe labellisée Ligue Contre le Cancer», 13009 Marseille, France.
⁶ Laboratory of Medical Parasitology, Biotechnology, and Biomolecules-LR16 IPT06, Institut Pasteur de Tunis, University of Tunis El Manar, Tunis 1002, Tunisia.
⁷ Department of Bio-Pathology, Paoli-Calmettes Institute, 13009 Marseille, France.
⁸ Laboratory of Neurophysiology Cellular Phytopathology and Biomolecules Valorisation (LR18ES03), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia.
⁹ Department of Surgical Oncology, Salah Azaiez Institute, Bab Saadoun, Tunis 1006, Tunisia.
¹⁰ Mycology, Pathologies and Biomarkers Laboratory (LR16ES05), Faculty of Sciences of Tunis, University of Tunis El Manar, Tunis 2092, Tunisia.
¹¹ Medical Oncology Service, Hospital of Ariana, Ariana 2080, Tunisia.
¹² Medicine School, Aix-Marseille University, 13005 Marseille, France.
¹³ Department of Medical Oncology, Paoli-Calmettes Institute, 13009 Marseille, France.

Abstract

Inflammatory breast cancer (IBC) is the most pro-metastatic form of breast cancer (BC). We previously demonstrated that protein overexpression of Myristoylated Alanine-Rich C Kinase Substrate (MARCKS) protein was associated with shorter survival in IBC patients. MARCKS has been associated with the PI3K/AKT pathway. MARCKS inhibitors are in development. Our objective was to investigate MARCKS, expressed preferentially in IBC that non-IBC (nIBC), as a novel potential therapeutic target for IBC. The biologic activity of MPS, a MARCKS peptide inhibitor, on cell proliferation, migration, invasion, and mammosphere formation was evaluated in IBC (SUM149 and SUM190) and nIBC (MDA-MB-231 and MCF7) cell lines, as well as its effects on protein expression in the PTEN/AKT and MAPK pathways. The prognostic relevance of MARCKS and phosphatase and tensin homolog (PTEN) protein expression as a surrogate marker of metastasis-free survival (MFS) was evaluated by immunohistochemistry (IHC) in a retrospective series of archival tumor samples derived from 180 IBC patients and 355 nIBC patients. In vitro MPS impaired cell proliferation, migration and invasion, and mammosphere formation in IBC cells. MARCKS inhibition upregulated PTEN and downregulated pAKT and pMAPK expression in IBC cells, but not in nIBC cells. By IHC, MARCKS expression and PTEN expression were negatively correlated in IBC samples and were associated with shorter MFS and longer MFS, respectively, in multivariate analysis. The combination of MARCKS-/PTEN+ protein status was associated with longer MFS in IBC patient only (p = 8.7 × 10^-3), and mirrored the molecular profile (MARCKS-downregulated/PTEN-upregulated) of MPS-treated IBC cell lines. In conclusion, our results uncover a functional role of MARCKS implicated in IBC aggressiveness. Associated with the good-prognosis value of the MARCKS-/PTEN+ protein status that mirrors the molecular profile of MPS-treated IBC cell lines, our results suggest that MARCKS could be a potential therapeutic target in patients with MARCKS-positive IBC. Future preclinical studies using a larger panel of IBC cell lines, animal models and analysis of a larger series of clinical samples are warranted in order to validate our results.

Keywords: MARCKS; MPS treatment; PTEN; inflammatory breast cancer; mechanisms; metastasis-free survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Biological Products* / therapeutic use
Humans
Inflammatory Breast Neoplasms* / drug therapy
Inflammatory Breast Neoplasms* / pathology
Myristoylated Alanine-Rich C Kinase Substrate*
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins c-akt
Retrospective Studies
Tensins

Substances

Biological Products
MARCKS protein, human
Tensins
Myristoylated Alanine-Rich C Kinase Substrate
Proto-Oncogene Proteins c-akt

Grants and funding

This research was funded by Institut Paoli-Calmettes, la Ligue Nationale Contre le Cancer (Label Ligue EL2022 to F.B.), and Le Prix Ruban Rose 2020 (to F.B.), also by the “projet de recherche mixtefranco-tunisien “ComitéMixte de Coopération Universitaire (CMCU) PHC Utique” (15G0805 to M.Ma. and M.M., and by the funds of the Human Genetics Laboratory (LR99ES10) at the Faculty of Medicine of Tunis (to MK).