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

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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.

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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

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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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  1. Tianjin Key Laboratory of Protein Science, Department of Genetics and Cell Biology, College of Life Sciences, Nankai University, Tianjin, 300071, China

    Jin Zhang, Qianying Wang, Qing Wang, Jiangran Cao, Jiafu Sun & Zhengmao Zhu

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Zhang, J., Wang, Q., Wang, Q. et al. Mechanisms of resistance to estrogen receptor modulators in ER+/HER2− advanced breast cancer. Cell. Mol. Life Sci. 77, 559–572 (2020). https://doi.org/10.1007/s00018-019-03281-4

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