Antisense Oligonucleotide-Based Therapeutic against Menin for Triple-Negative Breast Cancer Treatment

Abstract

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.

Menin inhibition suppresses castration-resistant prostate cancer and enhances chemosensitivity

“…Here we demonstrate that Menin-ASO can inhibit AR-positive and negative CRPC growth in vitro and in vivo, to enhance chemotherapy sensitivity and can serve as an efficient tool to restore CRPC treatment sensitivity with a less toxic effect. Recently, we reported that Menin-ASO also delays tumor progression in triple-negative breast cancer (TNBC) [ 20 ]. Oligonucleotide-based therapeutics in oncology utilize their specific high binding affinity for key oncogenic mRNA targets that can be abnormally expressed or spliced.…”

“…To design the antisense oligonucleotides (ASOs) targeting the entire Menin mRNA, an R-based software was developed in our laboratory by Pascal Finetti (PDA16130, 2017) as previously described [ 20 ]. The program’s output gives information about the ASO list sequences with their GC level and genes list with significant similarity.…”

“…ASO transfections were performed as previously described [ 20 ]. To study effects on Menin proteasome degradation, cycloheximide (10 µg/ml) and MG132 (10 µmol/l) were added in a replaced medium for 4, 24, and 48 h at the end of the second transfection with ASOs.…”

“…Menin also regulates cell proliferation, apoptosis, and maintenance of genome integrity. Although Menin acts as a tumor suppressor in endocrine tissues [ 18 , 19 ], recent studies have shown that Menin could promote tumorigenesis in various neoplasms [ 9 , 20 ]. Recently, in a small series of cases, MEN1 was found overexpressed in CRPC [ 21 ].…”

New Advances in the Research of Resistance to Neoadjuvant Chemotherapy in Breast Cancer

“…Current studies have shown that inhibitors of the menin/MLL1 complex are effective in some cancers, but they are not effective in the treatment of breast cancer [141]. Recent studies have found that ASO targeting menin mRNA has a greater advantage than siRNA, and has a better curative effect in the treatment of triple-negative breast cancer [142]. More importantly, in vitro menin silencing can have a synergistic effect with the taxane drug docetaxel in neoadjuvant chemotherapy.…”