Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

Garcı́a-Becerra, Rocı́o; Santos, Nancy Dos; Díaz, Lorenza; Camacho, Javier

doi:10.3390/ijms14010108

Cited by 221 publications

(203 citation statements)

References 247 publications

Supporting

Mentioning

199

Contrasting

Order By: Relevance

“…This ERP status greatly affected the clinical efficacy, and even lead to the failure of clinical BC treatment. Recently, certain studies reported that ERP may be associated with the following factors: Certain receptors, such as human epidermal growth factor-2, insulin-like growth factor receptor and fibroblast growth factor receptor, the phosphoinositide 3-kinase-Akt signal pathway and the abnormal expression of associated microRNAs (9)(10)(11)(12)(13)(14)(15). However, these studies did not take the clinical factors into consideration.…”

Section: Introductionmentioning

confidence: 99%

Analysis of factors affecting endocrine therapy resistance in breast cancer

Zhang

Chen

2015

Oncology Letters

View full text Add to dashboard Cite

Abstract. The present study aimed to identify the factors involved in the resistance to endocrine therapy in breast cancer (BC) patients with a positive estrogen receptor status via the collection of clinical, pathological and immunohistochemical indices. A retrospective survey was performed in patients who experienced the relapse and metastasis of BC between November 2007 and March 2013. A total of 45 patients were enrolled, and the observational duration was 7-84 months. The Kaplan-Meier method was used to create a survival curve, while the log-rank test was used to analyze the survival curve and the Cox regression analysis was used to investigate the associated factors contributing to the resistance to endocrine therapy. Univariate analysis showed that the age of onset, the use of radiotherapy, the endocrine treatment program, and the expression levels of progesterone receptor (PR) and CerbB2 affected the impact of endocrine treatment. The Cox regression analysis indicated that the age of onset, the use of radiotherapy, and the expression levels of PR and CerbB2 affected the disease-free survival time after endocrine therapy. A young age of onset, not receiving radiotherapy, a low expression level of PR and a high expression level of CerbB2 were the risk factors involved in the resistance to endocrine therapy in patients with BC. IntroductionBreast cancer (BC) is a common malignancy that is a serious threat to the health of women. It has been reported that ~1.5 million women are diagnosed with BC annually in the world and that nearly 0.5 million succumb to this disease (1). With accumulating studies on BC, the therapeutic schemes for BC have become much more mature, evolving from the initial local excision to current surgery-based comprehensive treatments, including radiotherapy, chemotherapy, endocrine therapy, biological immune therapy and molecular-targeted therapy.The estrogen receptor (ER) is often found in BC and this cancer is consequently labeled as ER-positive (ERP). Furthermore, as the occurrence and development of BC is so closely associated with the expression of the ER (2), endocrine therapy has been widely used as an effective therapeutic method. In the past few decades, endocrine therapeutic drugs have significantly improved the clinical outcomes of BC patients, as well as their quality of life (3,4). Recently, two multi-center, large-scale, prospective clinical trials further established the positive effect of endocrine therapy in BC treatment (5,6).However, with the extension of endocrine treatment, certain studies found that a few BC patients showed resistance to endocrine therapy. The clinical data indicated that although there were BC-ERP patients who were suitable for endocrine therapy, ~30% of BC-ERP patients exhibited resistance to endocrine drugs in the early stages of treatment (primary resistance), and ~40% BC-ERP of patients showed the effectiveness of endocrine therapy prior to exhibiting gradually reduced sensitivity or resistance with the extension of treatment time (7,8). This E...

show abstract

Section: Introductionmentioning

confidence: 99%

Analysis of factors affecting endocrine therapy resistance in breast cancer

Zhang

Chen

2015

Oncology Letters

View full text Add to dashboard Cite

show abstract

“…Potential reasons for endocrine resistance include the following: Loss or modification of ERα expression; ERα mutation; the altered regulation of signaling pathways (phosphoinositide 3-kinase/protein kinase B/mechanistic target of rapamycin and cyclin-dependent kinase 4/6 signaling pathways); cross talk between the ER and growth factor receptor signaling pathways [human epidermal growth factor receptor 2 (HER2)]; altered expression of specific microRNAs; and interactions between the tumor microenvironment and host immune response. Although significant progress has been made in understanding the underlying molecular mechanisms of ligand-independent activation of the ER, the mechanisms of endocrine resistance remain unclear (4,5).…”

Section: Introductionmentioning

confidence: 99%

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

et al. 2017

View full text Add to dashboard Cite

Abstract. Tumor resistance to endocrine therapy triggers estrogen-independent cancer progression, which is a major obstacle to the successful treatment of hormone receptor positive breast cancer (BC). The underlying molecular mechanisms of endocrine resistance are not fully understood yet. The matricellular protein cysteine-rich angiogenic inducer 61 (Cyr61) is associated with tumor invasiveness and the induction of tumorigenesis in various malignancies in vivo and the induction of estrogen-independence and endocrine therapy resistance in BC. The present study evaluated the potential effects and clinical relevance of Cyr61 expression levels in 67 patients with primary non-metastatic BC. Immunohistochemical analysis of formalin-fixed paraffin-embedded tissue sections was performed, and the association between Cyr61 protein expression and clinicopathological factors and survival was analyzed. Cyr61 overexpression was revealed to be significantly associated with a positive estrogen receptor (ER)/progesterone receptor (PR) status (P=0.016) and to the molecular subtype of BC (P=0.039). Compared with patients without Cyr61 overexpression, patients with Cyr61 overexpression exhibited an increased recurrence rate (30.6 vs. 22.6%) and decreased long-term survival (10-year overall survival, 62.9 vs. 69.7%); however, these associations did not reach statistically significant levels in Cox regression model analysis. Similar results were identified in the subgroup analysis of patients with ER/PR positive BC. These results indicate that Cyr61 serves a role in the development of endocrine therapy resistance in BC and is thus a potential therapeutic target to overcome endocrine therapy resistance. However, additional long-term survival analyses with large patient populations are required.

show abstract

“…A number of mechanisms, including activation of cell survival, cell stress, and cell signaling pathways, have been proposed as drivers of acquired resistance (6,7 ). Recent deepsequencing studies have highlighted the importance of acquired mutations of the estrogen receptor 1 (ESR1) 6 gene in driving resistance. Key mutation hot spots identified include p.L536, p.Y537, and p.D538, which generate ligand-independent ER␣ transcriptional activity thought to be unresponsive to AIs (8 -12 ).…”

mentioning

confidence: 99%

“…The tumor microenvironment has been suggested as a major factor in conferring innate resistance to cancer therapies (1 ), whereas a large proportion of patients develop resistance while receiving systemic antiestrogens such as tamoxifen or estrogen deprivation therapies such as aromatase inhibitors (AIs) (2)(3)(4)(5). A number of mechanisms, including activation of cell survival, cell stress, and cell signaling pathways, have been proposed as drivers of acquired resistance (6,7 ). Recent deepsequencing studies have highlighted the importance of acquired mutations of the estrogen receptor 1 (ESR1) 6 gene in driving resistance.…”

mentioning

confidence: 99%

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

et al. 2015

View full text Add to dashboard Cite

BACKGROUND Activating mutations in the estrogen receptor 1 (ESR1) gene are acquired on treatment and can drive resistance to endocrine therapy. Because of the spatial and temporal limitations of needle core biopsies, our goal was to develop a highly sensitive, less invasive method of detecting activating ESR1 mutations via circulating cell-free DNA (cfDNA) and tumor cells as a “liquid biopsy.” METHODS We developed a targeted 23-amplicon next-generation sequencing (NGS) panel for detection of hot-spot mutations in ESR1, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA), tumor protein p53 (TP53), fibroblast growth factor receptor 1 (FGFR1), and fibroblast growth factor receptor 2 (FGFR2) in 48 patients with estrogen receptor-α–positive metastatic breast cancer who were receiving systemic therapy. Selected mutations were validated using droplet digital PCR (ddPCR). RESULTS Nine baseline cfDNA samples had an ESR1 mutation. NGS detected 3 activating mutations in ESR1, and 3 hot-spot mutations in PIK3CA, and 3 in TP53 in baseline cfDNA, and the ESR1 p.D538G mutation in 1 matched circulating tumor cell sample. ddPCR analysis was more sensitive than NGS and identified 6 additional baseline cfDNA samples with the ESR1 p.D538G mutation at a frequency of <1%. In serial blood samples from 11 patients, 4 showed changes in cfDNA, 2 with emergence of a mutation in ESR1. We also detected a low frequency ESR1 mutation (1.3%) in cfDNA of 1 primary patient who was thought to have metastatic disease but was clear by scans. CONCLUSIONS Early identification of ESR1 mutations by liquid biopsy might allow for cessation of ineffective endocrine therapies and switching to other treatments, without the need for tissue biopsy and before the emergence of metastatic disease.

show abstract

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

Cited by 221 publications

References 247 publications

Analysis of factors affecting endocrine therapy resistance in breast cancer

Analysis of factors affecting endocrine therapy resistance in breast cancer

Clinical relevance of Cyr61 expression in patients with hormone-dependent breast cancer

Noninvasive Detection of Activating Estrogen Receptor 1 (ESR1) Mutations in Estrogen Receptor–Positive Metastatic Breast Cancer

Contact Info

Product

Resources

About