Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis

Wu, Yanming; Zhang, Zhao; Cenciarini, Mauro E.; Proietti, Cecilia J.; Amasino, Matías; Hong, Tao; Yang, Mei; Liao, Yiji; Chiang, H. C.; Kaklamani, Virginia; Jeselsohn, Rinath; Vadlamudi, Ratna K.; Huang, Tim H.M.; Li, Rong; Angelis, Carmine De; Fu, Xiaoyong; Elizalde, Patricia V.; Schiff, Rachel; Brown, Myles; Xu, Kexin

doi:10.1158/0008-5472.can-17-1327

Cited by 86 publications

(76 citation statements)

References 36 publications

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“…Consistent with our hypothesis, we identified context-specific ERα-cofactor interactions: its interactions with GREB1, NRIP1, and GATA3 were only detected in MCF7P cells, and its interaction with NCOA5 and FOXA1 were stronger in TamR cells ( Figure 3D). Indeed, loss of interaction between ERα and GREB1 34 and overexpression of FOXA1 21 are known to associate with hormone resistance, further supporting the authenticity of our BioID data. Several AP1 family TFs were among the identified ERα-interacting proteins ( Figure 3D), we later on chose JUN to study AP1 function on GAIN enhancers, as it is a common component of JUN/FOS and JUN/JUN dimers 35 .…”

Section: Altered Interactions Between Erα and Gata3/ap1 And Their Binsupporting

confidence: 80%

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

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Acquired therapy resistance is a major problem for anticancer treatment, yet the underlying molecular mechanisms remain unclear. Using an established breast cancer cellular model for endocrine resistance, we show that hormone resistance is associated with enhanced phenotypic plasticity, indicated by a general downregulation of luminal/epithelial differentiation markers and upregulation of basal/mesenchymal invasive markers. Our extensive omics studies, including GRO-seq on enhancer landscapes, demonstrate that the global enhancer gain/loss reprogramming driven by the differential interactions between ERα and other oncogenic transcription factors (TFs), predominantly GATA3 and AP1, profoundly alters breast cancer transcriptional programs. Our functional studies in multiple biological systems including culture and xenograft models of MCF7 and T47D lines support a coordinate role of GATA3 and AP1 in enhancer reprogramming that promotes phenotypic plasticity and endocrine resistance. Collectively, our study implicates that changes in TF-TF and TF-enhancer interactions can lead to genome-wide enhancer reprogramming, resulting in transcriptional dysregulations that promote plasticity and cancer therapy-resistance progression.However, when patients with ERα-positive breast cancer receive endocrine therapies for a period of 5 years, more than 30% of these patients eventually develop resistance and disease recurrence 9, 10 . As loss of ERα expression during therapies or metastatic progression is only found in ≤10% of patients 9 , this hormone-receptor pathway remains a major research focus for additional targeted therapies.Substantial evidence suggests that changes of components along the ERα axis, such as mutations or altered expression of ERα itself or ERα-interacting cofactors, may reprogram the ERα-mediated transcriptome that underlie the development of endocrine resistance [11][12][13] . Differential ERα binding is 5 also associated with clinical breast cancer progression 14 . However, the underlying molecular mechanisms of transcriptome transitions mediated by ERα during breast cancer progression and endocrine resistance are not well known.Enhancers are important distal DNA regulatory elements that control temporal-or spatial-specific gene expression patterns during development and other biological processes [15][16][17] . Dysregulation of enhancer function is involved in many diseases, particularly in cancers. Our previous genome-wide ChIP-seq studies have revealed that E 2 /ERα regulates its target gene expression program primarily through binding at distal enhancers to dictate cell growth and endocrine response 18,19 . Emerging evidence has implicated the link of epigenetic alterations of ERα-bound enhancers to hormone resistance and cancer invasion 14,20 . Thus, investigating oncogenic mechanisms that lead to the alterations of the ERα cistrome is critical for both understanding cancer progression and identifying of potential new cancer therapies.In this study, we compared matched control and resistant cells lin...

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Section: Altered Interactions Between Erα and Gata3/ap1 And Their Binsupporting

confidence: 80%

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Zhang

Xue

et al. 2019

Preprint

Self Cite

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“…TAM has been widely used for treatment of ER + breast cancers in the clinic . However, TAM resistance is a huge challenge for clinical practice, and promotes breast cancer metastasis and death . Our previous studies and those of others have shown that DLG5 acts as a tumour suppressor in breast cancer, and its expression is up‐regulated in Luminal type, but not basal‐like, breast cancer .…”

Section: Discussionmentioning

confidence: 97%

DLG5 suppresses breast cancer stem cell‐like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression

Liu

et al. 2018

J Cellular Molecular Medi

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Tamoxifen (TAM) is a primary drug for treatment of estrogen receptor positive breast cancer. However, TAM resistance remains a serious threat to breast cancer patients and may be attributed to increased stemness of breast cancer. Here, we show that discs large homolog 5 (DLG5) expression is down‐regulated in TAM‐resistant breast cancer and cells. DLG5 silencing decreased the sensitivity to TAM and increased the frequency and stemness of CD44+/CD24− breast cancer stem cells (BCSCs) and TAZ, a transducer of the Hippo pathway, expression in MCF7 cells while DLG5 overexpression had opposite effects. TAZ silencing restored the sensitivity to TAM and reduced the frequency and stemness in TAM‐resistant breast cancer cells. Taken together, our data indicate that down‐regulated DLG5 expression increases the stemness of breast cancer cells by enhancing TAZ expression, contributing to TAM resistance in breast cancer.

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Section: Discussionmentioning

confidence: 99%

“…Despite the clear association between GREB1 and proliferation of breast cancer cells, expression of GREB1 has been correlated to better prognosis in ER+ breast cancer patients (16, 40). In a study that included only patients that received adjuvant tamoxifen monotherapy, higher GREB1 expression correlated with both prolonged disease-free survival and sensitivity to tamoxifen treatment (40). Similarly, in an in vitro model of tamoxifen resistance, MCF7 cells that were resistant to tamoxifen treatment had significantly less GREB1 expression compared to the parental line, suggesting GREB1 expression is lost in hormone-refractory breast cancer cells (16).…”

Section: Discussionmentioning

confidence: 99%

GREB1 regulates proliferation of estrogen receptor positive breast cancer through modulation of PI3K/Akt/mTOR signaling

Haines

Klingensmith

Burd

2019

Preprint

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19Over 70% of breast cancers express the estrogen receptor (ER) and depend on ER 20 activity for survival and proliferation. While hormone therapies that target receptor activity are 21 initially effective, patients invariably develop resistance which is often associated with activation 22 of the PI3K/Akt/mTOR pathway. While the mechanism by which estrogen regulates proliferation 23is not fully understood, one gene target of ER, growth regulation by estrogen in breast cancer 1 24 (GREB1), is required for hormone-dependent proliferation. However, the molecular function by 25 which GREB1 regulates proliferation is unknown. Herein, we validate that knockdown of GREB1 26 results in growth arrest and that exogenous GREB1 expression initiates oncogene-induced 27 senescence, suggesting that an optimal level of GREB1 expression is necessary for 28 proliferation of breast cancer cells. Under both of these conditions, GREB1 is able to regulate 29 signaling through the PI3K/Akt/mTOR pathway. GREB1 acts intrinsically through PI3K to 30 regulate PIP 3 levels and Akt activity. Critically, growth suppression of estrogen-dependent 31 breast cancer cells by GREB1 knockdown is rescued by expression of constitutively activated 32Akt. Together, these data identify a novel molecular function by which GREB1 regulates breast 33 cancer proliferation through Akt activation and provides a mechanistic link between estrogen 34 signaling and the PI3K pathway. 35 36

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Tamoxifen Resistance in Breast Cancer Is Regulated by the EZH2–ERα–GREB1 Transcriptional Axis

Cited by 86 publications

References 36 publications

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

DLG5 suppresses breast cancer stem cell‐like characteristics to restore tamoxifen sensitivity by inhibiting TAZ expression

GREB1 regulates proliferation of estrogen receptor positive breast cancer through modulation of PI3K/Akt/mTOR signaling

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