Dataset Information

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer.

ABSTRACT: The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased receptor tyrosine kinase signaling leading to activation of various intracellular pathways involved in signal transduction, proliferation and cell survival, including growth factor receptor tyrosine kinases human epidermal growth factor receptor-2, epidermal growth factor receptor, PI3K/AKT/mammalian target of rapamycin (mTOR), Mitogen activated kinase (MAPK)/ERK, fibroblast growth factor receptor, insulin-like growth factor-1 receptor; alterations in cell cycle and apoptotic machinery; Epigenetic modification including dysregulation of DNA methylation, histone modification, and nucleosome remodeling; and altered expression of specific microRNAs. Functional genomics has helped us identify a catalog of genetic and epigenetic alterations that may be exploited as potential therapeutic targets and biomarkers of response. New treatment combinations targeting ER and such oncogenic signaling pathways which block the crosstalk between these pathways have been proven effective in preclinical models. Results of recent clinical studies suggest that subsets of patients benefit from the combination of inhibitor targeting certain oncogenic signaling pathway with endocrine therapy. Especially, inhibition of the mTOR signaling pathway, a key component implicated in mediating multiple signaling cascades, offers a promising approach to restore sensitivity to endocrine therapy in breast cancer. We systematically reviewed important publications cited in PubMed, recent abstracts from ASCO annual meetings and San Antonio Breast Cancer Symposium, and relevant trials registered at ClinicalTrials.gov. We present the molecular mechanisms contributing to endocrine resistance, in particular focusing on the biological rationale for the clinical development of novel targeted agents in endocrine resistant breast cancer. We summarize clinical trials utilizing novel strategies to overcome therapeutic resistance, highlighting the need to better identify the appropriate patients whose diseases are most likely to benefit from these specific strategies.

SUBMITTER: Zhao M

PROVIDER: S-EPMC4127598 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer.

Zhao Meng M Ramaswamy Bhuvaneswari B

World journal of clinical oncology 20140801 3

The estrogen receptor (ER) pathway plays a critical role in breast cancer development and progression. Endocrine therapy targeting estrogen action is the most important systemic therapy for ER positive breast cancer. However its efficacy is limited by intrinsic and acquired resistance. Mechanisms responsible for endocrine resistance include deregulation of the ER pathway itself, including loss of ER expression, post-translational modification of ER, deregulation of ER co-activators; increased re ...[more]

PMID: 25114842

Similar Datasets

Project description:Proteomic profiling of the estrogen/tamoxifen-sensitive MCF-7 cell line and its partially sensitive (MCF-7/LCC1) and fully resistant (MCF-7/LCC9) variants was performed to identify modifiers of endocrine sensitivity in breast cancer. Analysis of the expression of 120 paired phosphorylated and non-phosphorylated epitopes in key oncogenic and tumor suppressor pathways revealed that STAT1 and several phosphorylated epitopes (phospho-STAT1(Tyr701) and phospho-STAT3(Ser727)) were differentially expressed between endocrine resistant and parental controls, confirmed by qRT-PCR and western blotting. The STAT1 inhibitor EGCG was a more effective inhibitor of the endocrine resistant MCF-7/LCC1 and MCF-7/LCC9 lines than parental MCF-7 cells, while STAT3 inhibitors Stattic and WP1066 were equally effective in endocrine-resistant and parental lines. The effects of the STAT inhibitors were additive, rather than synergistic, when tested in combination with tamoxifen in vitro. Expression of STAT1 and STAT3 were measured by quantitative immunofluorescence in invasive breast cancers and matched lymph nodes. When lymph node expression was compared to its paired primary breast cancer expression, there was greater expression of cytoplasmic STAT1 (?3.1 fold), phospho-STAT3(Ser727) (?1.8 fold), and STAT5 (?1.5 fold) and nuclear phospho-STAT3(Ser727) (?1.5 fold) in the nodes. Expression levels of STAT1 and STAT3 transcript were analysed in 550 breast cancers from publicly available gene expression datasets (GSE2990, GSE12093, GSE6532). When treatment with tamoxifen was considered, STAT1 gene expression was nearly predictive of distant metastasis-free survival (DMFS, log-rank p?=?0.067), while STAT3 gene expression was predictive of DMFS (log-rank p<0.0001). Analysis of STAT1 and STAT3 protein expression in a series of 546 breast cancers also indicated that high expression of STAT3 protein was associated with improved survival (DMFS, p?=?0.006). These results suggest that STAT signaling is important in endocrine resistance, and that STAT inhibitors may represent potential therapies in breast cancer, even in the resistant setting.

Project description:Despite the effectiveness of endocrine therapies in estrogen receptor positive (ER+) breast cancer, approximately 40% of patients relapse. Previously, we identified the Focal-adhesion kinase canonical pathway as a major contributor of resistance to estrogen deprivation and cellular-sarcoma kinase (c-src) as a dominant gene in this pathway. Dasatinib, a pan-src inhibitor, has recently been used in clinical trials to treat ER+ patients but has shown mixed success. In the following study, using isogenic cell line models, we provide a potential explanation for these findings and suggest a sub-group that may benefit. A panel of isogenic cell lines modelling resistance to aromatase inhibitors (LTED) and tamoxifen (TAMR) were assessed for response to dasatinib ± endocrine therapy. Dasatinib caused a dose-dependent decrease in proliferation in MCF7-TAMR cells and resensitized them to tamoxifen and fulvestrant but not in HCC1428-TAMR. In contrast, in estrogen-deprived conditions, dasatinib increased the proliferation rate of parental-MCF7 cells and had no effect on MCF7-LTED or HCC1428-LTED. Treatment with dasatinib caused a decrease in src-phosphorylation and inhibition of downstream pathways, including AKT and ERK1/2 in all cell lines tested, but only the MCF7-TAMR showed a concomitant decrease in markers of cell cycle progression. Inhibition of src also caused a significant decrease in cell migration in both MCF7-LTED and MCF7-TAMR cells. Finally, we showed that, in MCF7-TAMR cells, in contrast to tamoxifen sensitive cell lines, ER is expressed throughout the cell rather than being restricted to the nucleus and that treatment with dasatinib resulted in nuclear shuttling of ER, which was associated with an increase in ER-mediated transcription. These data suggest that src has differential effects in endocrine-resistant cell lines, particularly in tamoxifen resistant models, with low ER genomic activity, providing further evidence of the importance of patient selection for clinical trials testing dasatinib utility in ER+ breast cancer.

Dataset Information

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer.

Publications

Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets