Molecular Mechanisms of Endocrine Resistance

Fu, Xiaoyong; Angelis, Carmine De; Veeraraghavan, Jamunarani; Osborne, C. Kent; Schiff, Rachel

doi:10.1007/978-3-319-99350-8_11

Cited by 7 publications

(9 citation statements)

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“…HER2 amplification and activation have been recognized as major contributors to anti-estrogen therapy resistance; however, the underlying molecular mechanisms are not fully understood (Shou et al, 2004;Fu et al, 2019). Given the co-amplification and correlation between HER2 status and the expression of MED1 in breast cancers, the role of MED1 in antiestrogen resistance was further examined.…”

Section: Med1 In Anti-estrogen Resistancementioning

confidence: 99%

“…Unfortunately, therapeutic resistance frequently occurs in these patients. Nearly half of all the ERpositive breast cancer patients experience de novo or acquired resistance to the treatment (Shou et al, 2004;Fu et al, 2019). In addition, the unwanted side effects on other estrogen-responsive tissues of the patients pose a major hindrance for treatment effectiveness (Kedar et al, 1994;Mourits et al, 2001;Eastell et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Leonard

Zhang

2019

J. Zhejiang Univ. Sci. B

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Breast cancer, one of the most frequent cancer types, is a leading cause of death in women worldwide. Estrogen receptor (ER) α is a nuclear hormone receptor that plays key roles in mammary gland development and breast cancer. About 75% of breast cancer cases are diagnosed as ER-positive; however, nearly half of these cancers are either intrinsically or inherently resistant to the current anti-estrogen therapies. Recent studies have identified an ER coactivator, Mediator Subunit 1 (MED1), as a unique, tissue-specific cofactor that mediates breast cancer metastasis and treatment resistance. MED1 is overexpressed in over 50% of human breast cancer cases and co-amplifies with another important breast cancer gene, receptor tyrosine kinase HER2. Clinically, MED1 expression highly correlates with poor disease-free survival of breast cancer patients, and recent studies have reported an increased frequency of MED1 mutations in the circulating tumor cells of patients after treatment. In this review, we discuss the biochemical characterization of MED1 and its associated MED1/Mediator complex, its crosstalk with HER2 in anti-estrogen resistance, breast cancer stem cell formation, and metastasis both in vitro and in vivo. Furthermore, we elaborate on the current advancements in targeting MED1 using state-of-the-art RNA nanotechnology and discuss the future perspectives as well.

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Section: Med1 In Anti-estrogen Resistancementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Leonard

Zhang

2019

J. Zhejiang Univ. Sci. B

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“…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 .…”

mentioning

confidence: 99%

“…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 .…”

mentioning

confidence: 99%

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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“…The discovery that HER2 amplification induces endocrine therapy resistance in ER + breast cancer spurred research into other means of HER2 activation. These studies identified HER2 mutation and phosphorylation as mechanisms by which ER + HER2 non-amplified (henceforth referred to as ER + HER2 -) breast cancer cells could resist endocrine treatment 2,11 . However, translation of these findings proved challenging with results from clinical trials not living up to preclinical promise 3,6 .…”

Section: Introductionmentioning

confidence: 99%

Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

Punturi

Şeker

Devarakonda

et al. 2020

Preprint

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One Sentence Summary: Defective mismatch repair activates HER2 in HER2-negative breast cancer cells and renders them susceptible to HER2 inhibitors. Abstract: Estrogen receptor positive (ER + ) breast cancer is a leading cause of cancer-related death globally. Resistance to standard of care endocrine treatment occurs in at least 30% of ER + breast cancer patients resulting in ~40,000 deaths every year in the US alone. Preclinical studies strongly implicate activation of growth factor receptor, HER2 in endocrine treatment resistance of ER + breast cancer that is HER2at diagnosis 1,2 . However, clinical trials of pan-HER inhibitors in ER + /HER2patients have disappointed, likely due to a lack of predictive biomarkers 3-6 . Here we demonstrate that loss of MLH1, a principal mismatch repair gene, causally activates HER2 in ER + /HER2breast cancer upon endocrine treatment. Additionally, we show that HER2 activation is indispensable for endocrine treatment resistant growth of MLH1cells in vitro and in vivo. Consequently, inhibiting HER2 restores sensitivity to endocrine treatment in multiple experimental models including patient-derived xenograft tumors. Patient data from multiple clinical datasets (TCGA, METABRIC, Alliance (Z1031) and E-GEOD-28826) supports an association between MLH1 loss, HER2 upregulation, and sensitivity to trastuzumab in endocrine treatment-resistant ER + /HER2patients. These results provide strong rationale that MLH1 could serve as a first-in-class predictive marker of sensitivity to combinatorial treatment with endocrine drugs and HER inhibitors in endocrine treatment-resistant ER + /HER2breast cancer patients. Implications of this study extend beyond breast cancer to Lynch Syndrome cancers. [Main Text: ]

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Molecular Mechanisms of Endocrine Resistance

Cited by 7 publications

References 294 publications

Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

Estrogen receptor coactivator Mediator Subunit 1 (MED1) as a tissue-specific therapeutic target in breast cancer

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

Mismatch repair deficiency predicts response to HER2 blockade in HER2-negative breast cancer

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