ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer

Manna, Sukumar; Bostner, Josefine; Sun, Yangying; Miller, Lance D.; Alayev, Anya; Schwartz, Naomi; Lager, Elin; Fornander, Tommy; Nordenskjöld, Bo; Yu, Jane; Stål, Olle; Holz, Marina K.

doi:10.1158/1078-0432.ccr-15-0857

Cited by 46 publications

(39 citation statements)

References 43 publications

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“…The exact mechanism for how FOXC1 regulated ER α was still not clear and more studies were needed to focus on the mechanism in the future. Breast cancer cells which expressed ER α are sensitive to E2 stimulation and tamoxifen treatment, such as MCF‐7 and T47D cells . The expression of ER α was reduced when expression of FOXC1 was increased in MCF‐7‐FOXC1 and T47D‐FOXC1, while expression of ER α was increased when expression of FOXC1 was reduced in BT549 FOXC1 shRNA and HCC1806 FOXC1 shRNA.…”

Section: Discussionmentioning

confidence: 99%

FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer

Wang

et al. 2016

Cancer Medicine

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FOXC1 is a member of Forkhead box transcription factors that participates in embryonic development and tumorigenesis. Our previous study demonstrated that FOXC1 was highly expressed in triple‐negative breast cancer. However, it remains unclear what is the relation between FOXC1 and ERα and if FOXC1 regulates expression of ERα. To explore relation between FOXC1 and ERα and discover regulation of ERα expression by FOXC1 in breast cancer, we analyzed data assembled in the Oncomine and TCGA, and found that there was significantly higher FOXC1 expression in estrogen receptor‐negative breast cancer than that in estrogen receptor‐positive breast cancer. Overexpression of FOXC1 reduced expression of ERα and cellular responses to estradiol (E2) and tamoxifen in the MCF‐7 FOXC1 and T47D FOXC1 cells, while knockdown of FOXC1 induced expression of ERα and improved responses to estradiol (E2) and tamoxifen in BT549 FOXC1 shRNA and HCC1806 FOXC1 shRNA cells. In addition, overexpression of FOXC1 reduced expression of progesterone receptor (PR), Insulin receptor substrate 1 (IRS1), and XBP1 (X‐Box Binding Protein 1) and significantly reduced luciferase activity caused by E2 using ERE luciferase reporter assay. These results suggested that FOXC1 regulated expression of ERα and affected sensitivity of tamoxifen treatment in breast cancer, and that FOXC1 may be used as a potential therapeutic target in ERα‐negative breast cancer.

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Section: Discussionmentioning

confidence: 99%

FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer

Wang

et al. 2016

Cancer Medicine

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“…The top 5 MMTRs in Basal-Like unique pathways (SREBF1, ESRRG, ESRRA, RFX2, and SREBF2) differ from those found to be associated with the Luminal A unique pathways (IRF8, OVOL1, THAP1, GATA1, and TFAP2C). Additionally, those MMTRs associated with pathways dysregulated across all subtypes were different from those unique to the Basal-like and Luminal A (HNF4A, ESRRA, HNF4G, RARA, and EP300), with the exception of one (ESRRA), which has been linked to all types of BRCA 57 . Further, the expression levels of these MMTRs cluster out patients based on the subtype of BRCA with which they are associated (Fig 7C), where Basal patients are indicated in black and Luminal A patients are indicated in yellow.…”

Section: Resultsmentioning

confidence: 95%

Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas

Rosario

Long

Affronti

et al. 2018

Preprint

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Understanding the levels of metabolic dysregulation in different disease settings is vital for the safe and effective incorporation of metabolism-targeted therapeutics in the clinic. Using transcriptomic data from 10,704 tumor and normal samples from The Cancer Genome Atlas, across 26 disease sites, we developed a novel bioinformatics pipeline that distinguishes tumor from normal tissues, based on differential gene expression for 114 metabolic pathways. This pathway dysregulation was confirmed in separate patient populations, further demonstrating the robustness of this approach. A bootstrapping simulation was then applied to assess whether these alterations were biologically meaningful, rather than expected by chance. We provide distinct examples of the types of analysis that can be accomplished with this tool to understand cancer specific metabolic dysregulation, highlighting novel pathways of interest in both common and rare disease sites. Utilizing a pathway mapping approach to understand patterns of metabolic flux, differential drug sensitivity, can accurately be predicted. Further, the identification of Master Metabolic Transcriptional Regulators, whose expression was highly correlated with pathway gene expression, explains why metabolic differences exist in different disease sites. We demonstrate these also have the ability to segregate patient populations and predict responders to different metabolism-targeted therapeutics.

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“…Estrogen-related receptor-α (ERRα), a member of the orphan nuclear receptor family, is closely related to ERα and plays an important role in cellular metabolism [108]. While ERRα has been associated with endocrine resistance, ERRα level could also predict tamoxifen sensitivity in TNBC [109]. TNBC cells express high levels of ERRα, and it was shown to negatively regulate S6K1 expression by directly binding to its promoter [110].…”

Section: Involvement Of S6ks In Triple-negative Breast Cancermentioning

confidence: 99%

Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

Sridharan

Basu

2020

IJMS

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The mechanistic target of rapamycin (mTOR) is a master regulator of protein translation, metabolism, cell growth and proliferation. It forms two complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2). mTORC1 is frequently deregulated in many cancers, including breast cancer, and is an important target for cancer therapy. The immunosuppressant drug rapamycin and its analogs that inhibit mTOR are currently being evaluated for their potential as anti-cancer agents, albeit with limited efficacy. mTORC1 mediates its function via its downstream targets 40S ribosomal S6 kinases (S6K) and eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1). There are two homologs of S6K: S6K1 and S6K2. Most of the earlier studies focused on S6K1 rather than S6K2. Because of their high degree of structural homology, it was generally believed that they behave similarly. Recent studies suggest that while they may share some functions, they may also exhibit distinct or even opposite functions. Both homologs have been implicated in breast cancer, although how they contribute to breast cancer may differ. The purpose of this review article is to compare and contrast the expression, structure, regulation and function of these two S6K homologs in breast cancer.Most of the earlier studies focused on p70 S6K1 or S6K1 as the downstream target of mTORC1. It was believed that due to structural similarities, S6K1 and S6K2 share redundant functions. Recent studies, however, challenge this notion [21][22][23][24][25]. Both homologs have been implicated in breast cancer, although they may play distinct roles [26,27]. In this review article, we briefly describe differences in structural aspects, regulation and cellular functions of these two homologs prior to discussing their distinct roles in breast cancer. Structure of S6KsBoth S6K1 and S6K2 exhibit a modular structure consisting of an N-terminal regulatory region, the kinase domain, followed by the kinase extension domain and a C-terminal regulatory region harboring the autoinhibitory/pseudosubstrate domain (Figure 1). While they share over 80% homology in the amino acid sequence of their kinase domains, as well as a high degree of similarity in the adjacent kinase extension and pseudosubstrate or autoinhibitory domains with conserved sites critical for their activation [16,17], important differences exist in the extreme N-and C-terminal regions. S6K1 possesses a C-terminal PDZ-binding domain, which promotes association with the actin cytoskeleton [28], whereas S6K2 but not S6K1 harbors a functional nuclear localization signal (NLS) and a proline-rich domain, which may promote interaction with the SH3-domain containing proteins at its C-terminus [16] (Figure 1). It is believed that these key differences between S6K1 and S6K2 will result in differential localization and binding partners and hence distinct functions for the two proteins [21].

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ERRα Is a Marker of Tamoxifen Response and Survival in Triple-Negative Breast Cancer

Cited by 46 publications

References 43 publications

FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer

FOXC1 is associated with estrogen receptor alpha and affects sensitivity of tamoxifen treatment in breast cancer

Pan-cancer analysis of transcriptional metabolic dysregulation using The Cancer Genome Atlas

Distinct Roles of mTOR Targets S6K1 and S6K2 in Breast Cancer

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