Estrogen receptor (ER) α mutations in breast cancer: hidden in plain sight

Fuqua, Suzanne A.W.; Gu, Guowei; Rechoum, Yassine

doi:10.1007/s10549-014-2847-4

Cited by 73 publications

(57 citation statements)

References 60 publications

(92 reference statements)

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“…These data suggest that the ICI-resistant LCC9 cells are still reliant on ERα-regulated cell survival signals which are presumably activated in a ligand-independent manner [9]. The ligand-independent activation of ERα due to somatic mutations [29,30] or as yet unidentified mechanisms have made targeting ERα in the endocrine therapy resistant breast cancer cells very challenging. Therefore, our finding that H19 regulates ERα gene expression in ETR cells has great clinical significance.…”

Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Basak

Chatterjee

Bhat

et al. 2018

Cell Physiol Biochem

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Background/Aims: Blocking estrogen signaling with endocrine therapies (Tamoxifen or Fulverstrant) is an effective treatment for Estrogen Receptor-α positive (ER⁺) breast cancer tumours. Unfortunately, development of endocrine therapy resistance (ETR) is a frequent event resulting in disease relapse and decreased overall patient survival. The long noncoding RNA, H19, was previously shown to play a significant role in estrogen-induced proliferation of both normal and malignant ER⁺ breast epithelial cells. We hypothesized that H19 expression is also important for the proliferation and survival of ETR cells. Methods: Here we utilized established ETR cell models; the Tamoxifen (Tam)-resistant LCC2 and the Fulvestrant and Tam cross-resistant LCC9 cells. Gain and loss of H19 function were achieved through lentiviral transduction as well as pharmacological inhibitors of the Notch and c-Met receptor signaling pathways. The effects of altered H19 expression on cell viability and ETR were assessed using three-dimensional (3D) organoid cultures and 2D co-cultures with low passage tumour-associated fbroblasts (TAFs). Results: Here we report that treating ETR cells with Tam or Fulvestrant increases H19 expression and that it’s decreased expression overcomes resistance to Tam and Fulvestrant in these cells. Interestingly, H19 expression is regulated by Notch and HGF signaling in the ETR cells and pharmacological inhibitors of Notch and c-MET signaling together significantly reverse resistance to Tam and Fulvestrant in an H19-dependent manner in these cells. Lastly, we demonstrate that H19 regulates ERα expression at the transcript and protein levels in the ETR cells and that H19 protects ERα against Fulvestrant-mediated downregulation of ERα protein. We also observed that blocking Notch and the c-MET receptor signaling also overcomes Fulvestrant and Tam resistance in 3D organoid cultures by decreasing ERα and H19 expression in the ETR cells. Conclusion: In endocrine therapy resistant breast cancer cells Fulvestrant is ineffective in decreasing ERα levels. Our data suggest that in the ETR cells, H19 expression acts as an ER modulator and that its levels and subsequently ERα levels can be substantially decreased by blocking Notch and c-MET receptor signaling. Consequently, treating ETR cells with these pharmacological inhibitors helps overcome resistance to Fulvestrant and Tamoxifen.

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Section: Discussionmentioning

confidence: 99%

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Basak

Chatterjee

Bhat

et al. 2018

Cell Physiol Biochem

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“…Heterogeneous protein function may foster tumor adaptation and may lead to drug resistance. 57,58 Thus, it is important to analyze tumor cells to obtain significant information. Considering the limitations of tumor biopsies, CTCs are expected to represent the full spectrum of the primary tumor and metastases and to play a role in guiding realtime drug selection.…”

Section: Heterogeneity Analysis Of Ctcs For Personalized Medicinementioning

confidence: 99%

Progress of Circulating Tumor Cells in Cancer Management

Zhang

Wang

Guan

et al. 2015

Technol Cancer Res Treat

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Circulating tumor cells are low-frequency cells that are shed into the peripheral bloodstream from a primary solid tumor and/or metastasis. Although these cells were recognized initially in 1869, it is only in the past 2 decades that they have been isolated for use as a surrogate biomarker to monitor response to therapy, evaluate prognosis, detect tumor mutations, assist in selecting personalized medicine, and enable earlier cancer diagnosis.

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“…For example, recent studies show that ESR1 mutations occur in metastatic sites of disease from ER-positive breast cancers, suggesting a causative role for ESR1 mutations in endocrine-resistance but not carcinogenesis of the primary tumor. 2 In fact, clonal evolution leading to mutationally distinct and heterogeneous tumor populations is a well-described phenomenon. 3 Whether targeting one specific driver mutation in the metastatic setting will afford clinical benefit is unknown.…”

Section: Clinical Utilitymentioning

confidence: 99%

Gene Mutation Profiling of Breast Cancers for Clinical Decision Making

Stearns

Park

2015

JAMA Oncol

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Recent advances in molecular profiling allow for a rapid and relatively inexpensive assessment of multiple altered genes or gene products from small amounts of tumor tissues or blood. The challenge ahead is how to properly incorporate these results into clinical practice, and how to providepatientswiththebestpossibleyetevidence-based care. Herein, we provide a brief overview of genetic mutation profiling with a focus on next-generation sequencing (NGS) and possible clinical utility.

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Estrogen receptor (ER) α mutations in breast cancer: hidden in plain sight

Cited by 73 publications

References 60 publications

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Long Non-Coding RNA H19 Acts as an Estrogen Receptor Modulator that is Required for Endocrine Therapy Resistance in ER+ Breast Cancer Cells

Progress of Circulating Tumor Cells in Cancer Management

Gene Mutation Profiling of Breast Cancers for Clinical Decision Making

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