Antisense Oligonucleotide-Based Therapeutic against Menin for Triple-Negative Breast Cancer Treatment
Dang Tan Nguyen,
Thi Khanh Le,
Clément Paris,
Chaïma Cherif,
Stéphane Audebert,
Sandra Oluchi Udu-Ituma,
Sébastien Benizri,
Philippe Barthélémy,
François Bertucci,
David Taïeb,
Palma Rocchi
Affiliations
Dang Tan Nguyen
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Thi Khanh Le
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Clément Paris
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Chaïma Cherif
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Stéphane Audebert
Marseille Protéomique, Centre de Recherche en Cancérologie de Marseille, INSERM, CNRS, Institut Paoli-Calmettes, Aix-Marseille University, 13009 Marseille, France
Sandra Oluchi Udu-Ituma
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Sébastien Benizri
ARNA Laboratory, INSERM U1212, CNRS UMR 5320, University of Bordeaux, 33076 Bordeaux, France
Philippe Barthélémy
ARNA Laboratory, INSERM U1212, CNRS UMR 5320, University of Bordeaux, 33076 Bordeaux, France
François Bertucci
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
David Taïeb
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
Palma Rocchi
Predictive Oncology Laboratory, Centre de Recherche en Cancérologie de Marseille, Inserm UMR 1068, CNRS UMR 7258, Institut Paoli-Calmettes, Aix-Marseille University, 27 Bd. Leï Roure, 13273 Marseille, France
The tumor suppressor menin has dual functions, acting either as a tumor suppressor or as an oncogene/oncoprotein, depending on the oncological context. Triple-negative breast cancer (TNBC) is characterized by the lack of expression of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (ERBB2/HER2) and is often a basal-like breast cancer. TNBC is associated with a dismal prognosis and an insufficient response to chemotherapies. Previously, menin was shown to play a proliferative role in ER-positive breast cancer; however, the functions of menin in TNBC remain unknown. Here, we have demonstrated that menin is expressed in various TNBC subtypes with the strongest expression in the TNBC Hs 578T cells. The depletion of menin by an antisense oligonucleotide (ASO) inhibits cell proliferation, enhances apoptosis in Hs 578T cells, highlighting the oncogenic functions of menin in this TNBC model. ASO-based menin silencing also delays the tumor progression of TNBC xenografts. Analysis of the menin interactome suggests that menin could drive TNBC tumorigenesis through the regulation of MLL/KMT2A-driven transcriptional activity, mRNA 3′-end processing and apoptosis. The study provides a rationale behind the use of ASO-based therapy, targeting menin in monotherapy or in combination with chemo or PARP inhibitors for menin-positive TNBC treatments.
