Dataset Information

Interactome of menin in triple negative breast cancer cell line

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 lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 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, functions of menin in TNBC remains unknown. We have demonstrated that menin is expressed in various TNBC subtypes with the strongest menin expression in the TNBC Hs 578T cells. Depletion of menin by antisense oligonucleotide inhibited cell proliferation, enhanced apoptosis, and induced cell cycle arrest in Hs 578T cells, highlighting oncogenic functions of menin in this TNBC model. To better understand the menin function, we performed AP-MS (Affinity Purification-Mass Spectrometry) using specific antibody against menin. Analysis of menin interactome suggested that menin could drive TNBC tumorigenesis through regulation of the MLL/KMT2A-driven transcriptional activity, mRNA 3’ end processing and apoptosis.

INSTRUMENT(S): Q Exactive Plus

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Breast Cancer

SUBMITTER: AUDEBERT Stephane

LAB HEAD: Rocchi Palma

PROVIDER: PXD024176 | Pride | 2021-09-10

REPOSITORIES: pride

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Dataset's files

Source:

			Action	DRS
	HS578T_Beads_Rep1.raw	Raw
	HS578T_Beads_Rep1_200110194517.raw	Raw
	HS578T_Beads_Rep1_200110222438.raw	Raw
	HS578T_Beads_Rep2.raw	Raw
	HS578T_Beads_Rep2_200111055744.raw	Raw

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Publications

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

Nguyen Dang Tan DT Le Thi Khanh TK Paris Clément C Cherif Chaïma C Audebert Stéphane S Udu-Ituma Sandra Oluchi SO Benizri Sébastien S Barthélémy Philippe P Bertucci François F Taïeb David D Rocchi Palma P

Biomedicines 20210708 7

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 w ...[more]

PMID: 34356858

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Project description:Triple negative breast cancer (TNBC) is a highly heterogeneous disease representing the most aggressive breast cancer (BC) subtype. Lack of Estrogen Receptor alpha (ERα), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2/neu) expression makes TNBC immune to common therapies, significantly limiting the treatment options and suggesting the need to identify novel therapeutic targets. It was previously reported that Estrogen Receptor beta (ERβ) is expressed in a fraction of TNBC patients, where its presence correlates with improved patient outcome. Recently, we demonstrated an oncosuppressive ERβ effect in TNBC cell models expressing exogenous ERβ. On the other hand, it was shown that ERβ is involved in miRNA-mediated gene regulation in hormone-responsive BC cells, suggesting similar effect also in TNBC. To verify this hypothesis, we performed small non-coding RNA (sncRNA) sequencing on three engineered cell lines belonging to different TNBC molecular subtypes. ERβ-specific changes of sncRNA profile revealed that the major part of deregulated molecules are subtype specific, with only few commonly regulated ones. In order to validate the obtained results, we performed sncRNA profiling of 12 ERβ positive and 32 ERβ negative TNBC tissues, whose receptor status was assessed by immunohistochemistry in our previous research. Also here, ERβ-specific group of deregulated sncRNAs was identified. Interestingly, comparison of obtained in vitro and in vivo results revealed 2 differentially expressed miRNAs, displaying the same behavior in all three analyzed cell lines and tissues. In concordance with our previous results, IPA signaling pathway analysis performed on genes targeted by deregulated miRNAs highlighted downregulation of cholesterol biosynthesis pathway and upregulation of several signaling processes. Taken together, these findings suggest that ERβ is able to exert its oncosuppressive role in TNBC through miRNA-mediated regulation of gene expression.

Project description:Current clinical guidelines suggest that breast cancers with low hormone receptor expression (LowHR) in 1% to 10% of tumor cells should be regarded as hormone receptor positive tumors. However, clinical data shows that patients with such tumors have a worse outcome compared to patients with hormone receptor expression above 10 %. Further, gene expression studies suggest that these tumors have a TNBC-like signature similar to triple negative breast cancers (TNBC). The goal of this study was to use DNA methylation-based classification to clarify the status for this infrequent but important patient subgroup. We performed whole genome DNA methylation profiling on 23 LowHR breast cancer specimens, including 13 samples with HER2 amplification and compared our results with a reference breast cancer cohort from The Cancer Genome Atlas. Unsupervised clustering and dimensionality reduction revealed that breast cancers with low hormone receptor expression that lacked HER2 amplification usually clustered with TNBC reference samples (8/10; “LowHR TNBC-like”). In contrast, most specimens with low hormone receptor expression and HER2 amplification grouped with hormone receptor positive cancers (11/13; “LowHR HRpos-like”). We observed highly similar DNA methylation patterns of LowHR TNBC-like samples and true TNBCs with almost no differential methylation. Furthermore, the Ki67 proliferation index of LowHR TNBC-like samples as well as clinical outcome parameters were more similar to TNBCs and differed from LowHR_HRpos-like cases. We here demonstrate that LowHR breast cancer comprises two molecularly distinct groups that can be separated by DNA methylation profiling. More clinical data is required for a definite classification of these tumors, but our data strongly suggests that LowHR TNBC-like samples are molecularly, histologically and clinically closely related to TNBC, while LowHR HRpos-like specimens are closely related to hormone receptor positive tumors.