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World J Clin Oncol. Aug 10, 2014; 5(3): 248-262
Published online Aug 10, 2014. doi: 10.5306/wjco.v5.i3.248
Mechanisms and therapeutic advances in the management of endocrine-resistant breast cancer
Meng Zhao, Bhuvaneswari Ramaswamy
Meng Zhao, Bhuvaneswari Ramaswamy, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Columbus, OH 43210, United States
Author contributions: Zhao M and Ramaswamy B contribute substantially to the conception and design, acquisition, analysis and interpretation of data; Zhao M drafts the article; Ramaswamy B revises it critically for important intellectual content; both authors give final approval of the version to be published.
Correspondence to: Bhuvaneswari Ramaswamy, MD, MRCP, Assistant Professor, Division of Medical Oncology, The Ohio State University Comprehensive Cancer Center, The Ohio State University’s Wexner Medical Center, Columbus, OH 43210, United States. bhuvaneswari.ramaswamy@osumc.edu
Telephone: +1-614-2936401 Fax: +1-614-2937529
Received: January 20, 2014
Revised: March 11, 2010
Accepted: June 20, 2014
Published online: August 10, 2014
Processing time: 193 Days and 0.2 Hours
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.

Keywords: Endocrine therapy; Endocrine resistance; Breast cancer; Therapeutic advances; Targeted therapy

Core tip: Endocrine therapy is the important systemic therapy for hormone receptor positive breast cancer. However, treatment resistance is common. Multiple mechanisms responsible for endocrine resistance have been identified over the past decade. New treatment combinations targeting estrogen receptor and growth factor receptor signaling which block the crosstalk between these pathways are effective in preclinical models and clinical studies. In this review, we summarize the complex genomic and epigenetic regulatory pathways involved in endocrine resistance, in particular focusing on the clinical trials utilizing novel strategies to overcome therapeutic resistance.