The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei

Nassa, Giovanni; Giurato, Giorgio; Salvati, Annamaria; Gigantino, Valerio; Pecoraro, Giovanni; Lamberti, Jessica; Rizzo, Francesca; Nyman, Tuula A.; Tarallo, Roberta; Weisz, Alessandro

doi:10.1038/s41597-019-0179-2

Cited by 22 publications

(19 citation statements)

References 39 publications

(49 reference statements)

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“…Furthermore, the main ER-interactors were NCOA3, GREB1, TRIM28 and HDAC1. No interaction with PLK1 was evident in any of the models and interrogation of publicly available data similarly showed no interaction 18 – 20 . In order to test this further, targeted co-IPs were performed in MCF7-LTED cells confirming the lack of interaction (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 77%

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Montaudon¹,

Nikitorowicz-Buniak²,

Sourd³

et al. 2020

Nat Commun

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A significant proportion of patients with oestrogen receptor (ER) positive breast cancers (BC) develop resistance to endocrine treatments (ET) and relapse with metastatic disease. Here we perform whole exome sequencing and gene expression analysis of matched primary breast tumours and bone metastasis-derived patient-derived xenografts (PDX). Transcriptomic analyses reveal enrichment of the G2/M checkpoint and up-regulation of Polo-like kinase 1 (PLK1) in PDX. PLK1 inhibition results in tumour shrinkage in highly proliferating CCND1 -driven PDX, including different RB-positive PDX with acquired palbociclib resistance. Mechanistic studies in endocrine resistant cell lines, suggest an ER-independent function of PLK1 in regulating cell proliferation. Finally, in two independent clinical cohorts of ER positive BC, we find a strong association between high expression of PLK1 and a shorter metastases-free survival and poor response to anastrozole. In conclusion, our findings support clinical development of PLK1 inhibitors in patients with advanced CCND1 -driven BC, including patients progressing on palbociclib treatment.

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Section: Resultsmentioning

confidence: 77%

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Montaudon¹,

Nikitorowicz-Buniak²,

Sourd³

et al. 2020

Nat Commun

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“…Another interesting essential gene involved in the estrogenic pathway is the DEAD box polypeptide 5 (DDX5), an ATP-dependent RNA helicase involved in several fundamental biological processes such as transcription, RNA processing, DNA damage-repair and splicing. This multifaceted activity depends on its capability to act as a coregulator of several oncogenic transcription factors as β-catenin, p53, STAT3 and ERα [73]. Acting as ERα coregulators, DDX5 promote receptor recruitment on estrogen-dependent genes as TFF1 and mediate interaction with (CBP)-p300, steroid receptor coactivator (SRC) family and RNA polymerase II (RNA Pol-II), showing an important role in the transcription machinery assembly [74].…”

Section: Functional Pathways Involving Estrogen Receptor-positive Essmentioning

confidence: 99%

“…In the field of estrogen-responsive BC being ERα the master regulator of estrogen signaling including a dense network of cointeractors, many proteomic studies have been carried out with the aim of identifying novel ERα-partners involved in the molecular bases of BC progression and to discover novel biomarkers and putative pharmacological targets [11,73,[85][86][87][88][89].…”

Section: Interaction Proteomics As Tool For Estrogen Signaling Proteimentioning

confidence: 99%

“…It regulates transcription of several genes involved in DNA repair, mediating interacting with RNA polymerase II holoenzyme and BRCA1 [94], and it is affected by anti-estrogenic treatment because it is clearly detected in very low quantity after ICI treatment than the E2 condition. The same group enlarged the knowledge of ERα molecular partners performing a purification and MS analysis on nuclear extract pre-treated or not with RNase, further characterizing the receptor interactome [73] FTSJ3 represent another interesting gene. It is a 2'-O-Me methyltransferase acting in associations with NIP7 for Ribosome biosynthesis.…”

Section: Interaction Proteomics As Tool For Estrogen Signaling Proteimentioning

confidence: 99%

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Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

Salvati

Gigantino

Nassa

et al. 2020

IJMS

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Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies.

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“…A C-terminus-TAP tagged ER (Ct-ER ) stably expressed in MCF-7 cells was used a "bait" to isolate multiprotein complexes that were then analyzed by LC-MS/MS and bioinformatics data analyses ( Figure 1A) in a workflow we already demonstrated suitable and robust for characterization of nuclear receptor interacting partners in cancer cells. [9,[11][12][13][14][15] MCF7 cells (Ct-ER and CTRL) nuclear extracts were subjected to TAP procedure as detailed in Experimental Section, Sup-porting Information. Three independent biological replicates for each experimental condition were performed and analyzed, in parallel, by mass spectrometry.…”

mentioning

confidence: 99%

Identification of Antiestrogen‐Bound Estrogen Receptor α Interactomes in Hormone‐Responsive Human Breast Cancer Cell Nuclei

et al. 2020

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Estrogen receptor alpha (ER) is a ligand-inducible transcription factor which mediates estrogen actions in hormone-responsive tumors and is targeted by effective anticancer therapies based on the ER antagonist ligands, selective estrogen receptor modulators (such as Tamoxifen/TAM) or disruptors (such as Fulvestrant/ICI). Despite its importance for cancer therapy, including acquired resistance to endocrine therapy, the molecular basis of ER response to different ligands is not fully known to date. Interaction proteomics shows great potential to identify and characterize molecular mechanisms of disease based on physical and functional protein-protein interaction networks. Tandem affinity purification coupled to mass spectrometry is applied here for mapping in hormone-responsive breast cancer cells nuclei, the ER interactomes, induced by each of the two classes of antiestrogens. The results provide new insights on the molecular bases for antiestrogen-mediated control of ER function and reveal new potential ways to overcome endocrine therapy resistance in cancer. Estrogens have been recognized as key modulators of the growth and differentiation of normal, premalignant, and malignant cell types, through interaction with nuclear estrogen receptors (ERs). Following estrogen stimulation, ERs undergo nuclear translocation regulating the expression of target genes via co-activators or

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The RNA-mediated estrogen receptor α interactome of hormone-dependent human breast cancer cell nuclei

Cited by 22 publications

References 39 publications

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

PLK1 inhibition exhibits strong anti-tumoral activity in CCND1-driven breast cancer metastases with acquired palbociclib resistance

Global View of Candidate Therapeutic Target Genes in Hormone-Responsive Breast Cancer

Identification of Antiestrogen‐Bound Estrogen Receptor α Interactomes in Hormone‐Responsive Human Breast Cancer Cell Nuclei

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