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.
Highlights
We have aimed to investigate the expression of menin in various Triple-negative breast cancer (TNBC) cells and assess the effects of specific antisense oligonucleotide (ASO)-driven menin inhibition on apoptosis and tumor progression in vitro and in vivo using the TNBC Hs 578T cell model
Cell viability was expressed as the percentage of absorbance of transfected cells compared to untreated cells
Further WB analysis revealed that ASO21-transfected cells (ASO21) downregulated menin in a dose-dependent manner (Figure 2b); ASO21 was used for further analyses in the study
Summary
Due to the absence of ER, PR, HER2 expressions, TNBC tumors are unresponsive to hormone therapy or HER2-directed treatment, and TNBC patients have limited susceptibility to chemotherapy; TNBC remains the most challenging breast cancer subtype to overcome [8]. The direct and specific inhibition of menin would represent an alternative approach and is expected to interrupt the diversity of oncogenic functions of menin To this purpose, we have developed antisense oligonucleotides (ASOs) against menin mRNAs. ASOs have several advantages over siRNAs, such as their sufficient cellular uptake without the need of transfection reagents, their easier synthesis and lower cost of production [25]. Menin has a dual role in breast cancer; whether menin functions as a tumor suppressor or menin has a proliferative activity in TNBC is completely unknown. We present the map of menin-interacting proteins identified by IP coupled MS, suggesting putative menin functions in TNBC
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