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Mechanisms of resistance to estrogen receptor modulators in ER+/HER2− advanced breast cancer

  • Jin Zhang
  • Qianying Wang
  • Qing Wang
  • Jiangran Cao
  • Jiafu Sun
  • Zhengmao ZhuEmail author
Review
  • 460 Downloads

Abstract

Endocrine therapy represents a mainstay adjuvant treatment of estrogen receptor-positive (ER+) breast cancer in clinical practice with an overall survival (OS) benefit. However, the emergence of resistance is inevitable over time and is present in one-third of the ER+ breast tumors. Several mechanisms of endocrine resistance in ER+/HER2− advanced breast cancers, through ERα itself, receptor tyrosine signaling, or cell cycle pathway, have been identified to be pivotal in endocrine therapy. The epigenetic alterations also contribute to ensuring tumor cells’ escape from endocrine therapies. The strategy of combined hormone therapy with targeted pharmaceutical compounds has shown an improvement of progression-free survival or OS in clinical practice, including three different classes of drugs: CDK4/6 inhibitors, selective inhibitor of PI3Kα and mTOR inhibitors. Many therapeutic targets of cell cycle pathway and cell signaling and their combination strategies have recently entered clinical trials. This review focuses on Cyclin D–CDK4/6–RB axis, PI3K pathway and HDACs. Additionally, genomic evolution is complex in tumors exposed to hormonal therapy. We highlight the genomic alterations present in ESR1 and PIK3CA genes to elucidate adaptive mechanisms of endocrine resistance, and discuss how these mutations may inform novel combinations to improve clinical outcomes in the future.

Keywords

Endocrine resistance ESR1mutation CDK4/6 inhibitor PI3K HDAC inhibitor 

Abbreviations

AIs

Aromatase inhibitors

CDK4

Cyclin-dependent kinase 4

CDK6

Cyclin-dependent kinase 6

DNMT

DNA methyltransferase

ER

Estrogen receptor

ETs

Endocrine therapies

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HR

Hormone receptor-positive

KDM

Histone demethylase

MAPK

Mitogen-activated protein kinase

NCoR

Nuclear corepressor

OS

Overall survival

PFS

Progression-free survival

PI3K

Phosphoinositide 3 kinase

RB

Retinoblastoma protein

RTKs

Receptor tyrosine kinases

SMRT

Silencing mediator for retinoid or thyroid hormone receptors

TET

Ten–eleven translocation

Notes

Acknowledgements

The work of the authors was supported by the National Natural Science Foundation of China (Grant No. 91649107), the Natural Science Foundation of Tianjin City of China (Grant No. 17JCYBJC24100).

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© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life SciencesNankai UniversityTianjinChina

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