Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

Aspros, Kirsten G M; Carter, Jodi M.; Hoskin, Tanya L.; Suman, Vera J.; Subramaniam, Malayannan; Emch, Michael J.; Ye, Zhenqing; Sun, Zhifu; Sinnwell, Jason P.; Thompson, Kevin J.; Tang, Xiaojia; Rodman, Esther; Wang, Xiyin; Nelson, Adam W; Chernukhin, Igor; Hamdan, Feda H.; Bruinsma, Elizabeth S.; Carroll, Jason S.; Fernández-Zapico, Martín E.; Johnsen, Steven A.; Kalari, Krishna R.; Huang, Haojie; Leon‐Ferre, Roberto A.; Couch, Fergus J.; Ingle, James N.; Goetz, Matthew P.; Hawse, John R.

doi:10.1038/s41523-022-00387-0

Cited by 14 publications

(23 citation statements)

References 82 publications

(90 reference statements)

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“…A molecular study demonstrated that the MafG promoter contained AP-1, E-box, and NF-κB binding sites. The transcription factors p50, p65, AP-1 family (c-Jun, c-Fos, Fos-B, Fra-1, Fra-2) and c-myc are recognized as oncogenes due to their capacities to maintain malignant cell survival and offer signals for unlimited proliferation [50][51][52]. These transcription factors are highly expressed in esophageal cancer, prostate cancer and gastric cancer [53][54][55].…”

Section: Regulation Of Mafs At the Transcriptional Levelmentioning

confidence: 99%

The role and regulation of Maf proteins in cancer

Deng

Zhang

et al. 2023

Biomark Res

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The Maf proteins (Mafs) belong to basic leucine zipper transcription factors and are members of the activator protein-1 (AP-1) superfamily. There are two subgroups of Mafs: large Mafs and small Mafs, which are involved in a wide range of biological processes, such as the cell cycle, proliferation, oxidative stress, and inflammation. Therefore, dysregulation of Mafs can affect cell fate and is closely associated with diverse diseases. Accumulating evidence has established both large and small Mafs as mediators of tumor development. In this review, we first briefly describe the structure and physiological functions of Mafs. Then we summarize the upstream regulatory mechanisms that control the expression and activity of Mafs. Furthermore, we discuss recent studies on the critical role of Mafs in cancer progression, including cancer proliferation, apoptosis, metastasis, tumor/stroma interaction and angiogenesis. We also review the clinical implications of Mafs, namely their potential possibilities and limitations as biomarkers and therapeutic targets in cancer.

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Section: Regulation Of Mafs At the Transcriptional Levelmentioning

confidence: 99%

The role and regulation of Maf proteins in cancer

Deng

Zhang

et al. 2023

Biomark Res

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“…For example, a recent study looking into a cohort of 567 TNBC tumors, found that ERβ was expressed in 18% of them. Possible mechanisms for ERβ mediated tumor suppression include the formation of co-repressor complexes that suppress the activity of oncogenic NFκB/RELA (p65) and thus inhibit p65 signaling ( 75 ). Additionally, Erβ has been found to downregulate the unfolded protein response (UPR), which enables the survival of cancer cell to endoplasmic reticulum stress induced by poor tumor vascularization ( 76 ).…”

Section: The Human Microbiome and Cancermentioning

confidence: 99%

Understanding and harnessing triple-negative breast cancer-related microbiota in oncology

2022

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Bacterial inhabitants of the body have the potential to play a role in various stages of cancer initiation, progression, and treatment. These bacteria may be distal to the primary tumour, such as gut microbiota, or local to the tissue, before or after tumour growth. Breast cancer is well studied in this context. Amongst breast cancer types, Triple Negative Breast Cancer (TNBC) is more aggressive, has fewer treatment options than receptor-positive breast cancers, has an overall worse prognosis and higher rates of reoccurrence. Thus, an in-depth understanding of the bacterial influence on TNBC progression and treatment is of high value. In this regard, the Gut Microbiota (GM) can be involved in various stages of tumour progression. It may suppress or promote carcinogenesis through the release of carcinogenic metabolites, sustenance of proinflammatory environments and/or the promotion of epigenetic changes in our genome. It can also mediate metastasis and reoccurrence through interactions with the immune system and has been recently shown to influence chemo-, radio-, and immune-therapies. Furthermore, bacteria have also been found to reside in normal and malignant breast tissue. Several studies have now described the breast and breast tumour microbiome, with the tumour microbiota of TNBC having the least taxonomic diversity among all breast cancer types. Here, specific conditions of the tumour microenvironment (TME) - low O2, leaky vasculature and immune suppression - are supportive of tumour selective bacterial growth. This innate bacterial ability could enable their use as delivery agents for various therapeutics or as diagnostics. This review aims to examine the current knowledge on bacterial relevance to TNBC and potential uses while examining some of the remaining unanswered questions regarding mechanisms underpinning observed effects.

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“…Numerous studies have reported the expression of a second form of the estrogen receptor, estrogen receptor beta (ERβ), in TNBC (6). Using a highly validated monoclonal antibody (7,8), we and others have demonstrated that ERβ1, the full length form of this receptor, is expressed in approximately 20% of primary TN breast tumors (6,(8)(9)(10). Tumoral expression of ERβ is generally associated with better prognostic factors such as lymph node negativity, enhanced responses to therapy, and improved patient outcomes such as improved diseasefree, metastasis-free, and overall survival (6,(10)(11)(12)(13).…”

Section: Introductionmentioning

confidence: 99%

“…Using a highly validated monoclonal antibody (7,8), we and others have demonstrated that ERβ1, the full length form of this receptor, is expressed in approximately 20% of primary TN breast tumors (6,(8)(9)(10). Tumoral expression of ERβ is generally associated with better prognostic factors such as lymph node negativity, enhanced responses to therapy, and improved patient outcomes such as improved diseasefree, metastasis-free, and overall survival (6,(10)(11)(12)(13). Ligand-mediated activation of ERβ has been shown to decrease proliferation, invasion, and migration of TNBC cells in vitro as well as tumor formation, growth, and metastatic spread in vivo (10,(14)(15)(16).…”

Section: Introductionmentioning

confidence: 99%

“…Tumoral expression of ERβ is generally associated with better prognostic factors such as lymph node negativity, enhanced responses to therapy, and improved patient outcomes such as improved diseasefree, metastasis-free, and overall survival (6,(10)(11)(12)(13). Ligand-mediated activation of ERβ has been shown to decrease proliferation, invasion, and migration of TNBC cells in vitro as well as tumor formation, growth, and metastatic spread in vivo (10,(14)(15)(16). Given these anticancer properties of ERβ in TNBC, it is critical to better understand the mechanisms by which it elicits these effects and the clinical situations in which ERβ targeted therapies are most likely to be effective.…”

Section: Introductionmentioning

confidence: 99%

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Disruption of estrogen receptor beta’s DNA binding domain impairs its tumor suppressive effects in triple negative breast cancer

Aspros

Emch²,

Wang³

et al. 2023

Front. Med.

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Triple negative breast cancer (TNBC) is an aggressive sub-type of the disease which accounts for a disproportionately high percentage of breast cancer morbidities and mortalities. For these reasons, a better understanding of TNBC biology is required and the development of novel therapeutic approaches are critically needed. Estrogen receptor beta (ERβ) is a reported tumor suppressor that is expressed in approximately 20% of primary TNBC tumors, where it is associated with favorable prognostic features and patient outcomes. Previous studies have shown that ERβ mediates the assembly of co-repressor complexes on DNA to inhibit the expression of multiple growth promoting genes and to suppress the ability of oncogenic transcription factors to drive cancer progression. To further elucidate the molecular mechanisms by which ERβ elicits its anti-cancer effects, we developed MDA-MB-231 cells that inducibly express a mutant form of ERβ incapable of directly binding DNA. We demonstrate that disruption of ERβ’s direct interaction with DNA abolishes its ability to regulate the expression of well characterized immediate response genes and renders it unable to suppress TNBC cell proliferation. Loss of DNA binding also diminishes the ability of ERβ to suppress oncogenic NFκB signaling even though it still physically associates with NFκB and other critical co-factors. These findings enhance our understanding of how ERβ functions in this disease and provide a model system that can be utilized to further investigate the mechanistic processes by which ERβ elicits its anti-cancer effects.

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Estrogen receptor beta repurposes EZH2 to suppress oncogenic NFκB/p65 signaling in triple negative breast cancer

Cited by 14 publications

References 82 publications

The role and regulation of Maf proteins in cancer

The role and regulation of Maf proteins in cancer

Understanding and harnessing triple-negative breast cancer-related microbiota in oncology

Disruption of estrogen receptor beta’s DNA binding domain impairs its tumor suppressive effects in triple negative breast cancer

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