Interaction Proteomics Identifies ERbeta Association with Chromatin Repressive Complexes to Inhibit Cholesterol Biosynthesis and Exert An Oncosuppressive Role in Triple-negative Breast Cancer

Triple-negative breast cancer (TNBC) is characterized by poor response to therapy and low overall patient survival. Recently, Estrogen Receptor beta (ERβ) has been found to be expressed in a fraction of TNBCs where, because of its oncosuppressive actions on the genome, it represents a potential therapeutic target, provided a better understanding of its actions in these tumors becomes available. To this end, the cell lines Hs 578T, MDA-MB-468 and HCC1806, representing the claudin-low, basal-like 1 and 2 TNBC molecular subtypes respectively, were engineered to express ERβ under the control of a Tetracycline-inducible promoter and used to investigate the effects of this transcription factor on gene activity. The antiproliferative effects of ERβ in these cells were confirmed by multiple functional approaches, including transcriptome profiling and global mapping of receptor binding sites in the genome, that revealed direct negative regulation by ERβ of genes, encoding for key components of cellular pathways associated to TNBC aggressiveness representing novel therapeutic targets such as angiogenesis, invasion, metastasis and cholesterol biosynthesis. Supporting these results, interaction proteomics by immunoprecipitation coupled to nano LC-MS/MS mass spectrometry revealed ERβ association with several potential nuclear protein partners, including key components of regulatory complexes known to control chromatin remodeling, transcriptional and post-transcriptional gene regulation and RNA splicing. Among these, ERβ association with the Polycomb Repressor Complexes 1 and 2 (PRC1/2), known for their central role in gene regulation in cancer cells, was confirmed in all three TNBC subtypes investigated, suggesting its occurrence independently from the cellular context. These results demonstrate a significant impact of ERβ in TNBC genome activity mediated by its cooperation with regulatory multiprotein chromatin remodeling complexes, providing novel ground to devise new strategies for the treatment of these diseases based on ligands affecting the activity of this nuclear receptor or some of its protein partners.

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Triple negative apocrine breast carcinoma has better prognosis despite poor response to neoadjuvant chemotherapy

10.21203/rs.3.rs-1242664/v1 ◽

2022 ◽

Author(s):

Taobo Hu ◽

Yiqiang Liu ◽

Xuejiao Lina Hu ◽

Guiyang Zhao ◽

Shu Wang ◽

...

Keyword(s):

Breast Cancer ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Poor Response ◽

Response To Therapy ◽

Breast Cancers ◽

Apocrine Carcinoma ◽

Cancer Specific Survival ◽

Invasive Ductal Breast Cancer ◽

Apocrine Differentiation

Abstract Background: Apocrine carcinoma is a rare subtype of invasive ductal breast cancer that shows apocrine differentiation and largely with triple negative immunohistology. Triple negative breast cancers are known to have a more aggressive clinical course. However, unlike the most other types, it is reported that triple negative apocrine carcinoma has a better prognosis. Due to scarcity of reported studies, our knowledges for its clinical behavior, prognosis and response to therapy are very limited. Methods: In this study, we retrospectively retrieved 41 triple negative apocrine carcinoma cases from our breast cancer database with an average follow up 32.8 months.Results: It was found that triple negative apocrine carcinoma had poorer response to neoadjuvant therapy, but better prognosis compared with other non-apocrine types of triple negative breast cancer. Meanwhile, triple negative apocrine carcinoma has a low proliferative nature as indicated by its low Ki67 index. Analysis of SEER database showed that chemotherapy did not improve breast cancer specific survival in TNAC patients. Conclusions: Our results suggest that triple negative apocrine carcinoma is a special subtype of triple negative breast cancer for which de-escalation of chemotherapy should be considered.

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Peer Review #2 of "Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene (v0.1)"

10.7287/peerj.6501v0.1/reviews/2 ◽

2019 ◽

Keyword(s):

Breast Cancer ◽

Peer Review ◽

Cancer Patients ◽

Chromatin Remodeling ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Genetic Alteration ◽

Breast Cancer Patients

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Peer Review #2 of "Tumor mutational profile of triple negative breast cancer patients in Thailand revealed distinctive genetic alteration in chromatin remodeling gene (v0.2)"

10.7287/peerj.6501v0.2/reviews/2 ◽

2019 ◽

Keyword(s):

Breast Cancer ◽

Peer Review ◽

Cancer Patients ◽

Chromatin Remodeling ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Genetic Alteration ◽

Breast Cancer Patients

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Small Non-Coding RNA Profiling Identifies miR-181a-5p as a Mediator of Estrogen Receptor Beta-Induced Inhibition of Cholesterol Biosynthesis in Triple-Negative Breast Cancer

Cells ◽

10.3390/cells9040874 ◽

2020 ◽

Vol 9 (4) ◽

pp. 874 ◽

Cited By ~ 5

Author(s):

Elena Alexandrova ◽

Jessica Lamberti ◽

Pasquale Saggese ◽

Giovanni Pecoraro ◽

Domenico Memoli ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Cell Lines ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Cholesterol Biosynthesis ◽

Regulation Of Gene Expression ◽

Estrogen Receptor Beta ◽

Tyrosine Kinase 2 ◽

Receptor Beta

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, representing the most aggressive breast cancer (BC) subtype with limited treatment options due to a lack of estrogen receptor alpha (ERα), progesterone receptor (PR), and Erb-B2 receptor tyrosine kinase 2 (HER2/neu) expression. Estrogen receptor beta (ERβ) is present in a fraction of TNBC patients, where its expression correlates with improved patient outcomes, supported by the fact that it exerts oncosuppressive effects in TNBC cell models in vitro. ERβ is involved in microRNA-mediated regulation of gene expression in hormone-responsive BC cells and could mediate its actions through small noncoding RNAs (sncRNAs) in TNBCs also. To verify this possibility, smallRNA sequencing was performed on three ERβ-expressing cell lines from different TNBC molecular subtypes. Several sncRNAs resulted modulated by ERβ, with a subset being regulated in a tumor subtype-independent manner. Interestingly, sncRNA profiling of 12 ERβ+and 32 ERβ− primary TNBC biopsies identified 7 microRNAs, 1 PIWI-interacting RNA (piRNA), and 1 transfer RNA (tRNA) differentially expressed in ERβ+ compared to ERβ− tumors and cell lines. Among them, miR-181a-5p was found to be overexpressed in ERβ+ tumors and predicted target key components of the cholesterol biosynthesis pathway previously found to be inhibited by ERβ in TNBC cells.

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