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The Unfolded Protein Response in Triple-Negative Breast Cancer

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The Unfolded Protein Response in Cancer

Part of the book series: Cancer Drug Discovery and Development ((CDD&D))

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Abstract

Triple-negative breast cancer (TNBC) is the designation of the diverse and highly aggressive breast cancers that lack the expression of estrogen receptor, progesterone receptor, and HER2. Due to the lack of recognized molecular targets for therapy, chemotherapy remains the primary established treatment for TNBC. In TNBC, numerous exogenous and intrinsic factors cause accumulation of misfolded or unfolded proteins in the endoplasmic reticulum (ER) to disrupt cellular proteostasis in a condition termed ER stress. As an adaptation, cells activate a network of pathways, the unfolded protein response (UPR), to manage ER stress. Chronic stress, a risk factor in cancer initiation and progression, keeps the UPR engaged while its apoptotic function gets gradually attenuated. The UPR has been increasingly recognized to have crucial roles both in physiological contexts and tumor pathology. In this review, we summarize the factors that may contribute to the regulation of the UPR in TNBC and its impact on various aspects of tumor biology. In addition, we review recent progress on the pharmacological targeting of the UPR, which holds therapeutic potential for TNBC intervention.

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Abbreviations

ATF4:

Activating transcription factor 4

ATF6:

Activating transcription factor 6

BC:

Breast cancer

BiP:

Binding immunoglobulin protein

BL:

Basal-like

CHOP:

C/EBP homologous protein

CREB3:

cAMP responsive element binding protein 3

CREB3L:

cAMP responsive element binding protein 3 like

DC:

Dendritic cells

DR5:

Death receptor 5

eIF2α:

Eukaryotic translation initiation factor 2 alpha

EMT:

Epithelial to mesenchymal transition

ER:

Endoplasmic reticulum

ERAD:

Endoplasmic reticulum-associated degradation

ERSE:

Endoplasmic reticulum stress element

FAS:

Fatty acid synthase

FFA:

Free fatty acid

FOXO:

Forkhead box O

GAAC:

General amino acid control

GADD34:

Growth arrest and DNA damage-inducible protein 34

GCN2:

General control nonderepressible 2

GEF:

Guanine nucleotide exchange factor

HIF1α:

Hypoxia-inducible factor 1α

HRI:

Heme-regulated eIF2α kinase

IM:

Immunomodulatory

IRE1α:

Inositol-requiring enzyme 1α

ISR:

Integrated stress response

JNK:

JUN N-terminal kinase

LAR:

Luminal androgen receptor

M:

Mesenchymal

MEF:

Mouse embryonic fibroblasts

MSL:

Mesenchymal stem-like

NRF2:

Nuclear factor erythroid 2-related factor 2

PDAC:

Pancreatic ductal adenocarcinoma

PDX:

Patient-derived xenograft

PERK:

Protein kinase RNA (PKR)-like ER kinase

PHD3:

Prolyl-4-hydroxylase domain 3

PI3K:

Phosphoinositide 3-kinase

PR:

Progesterone receptor

RIDD:

Regulated IRE1α-dependent decay

ROS:

Reactive oxygen species

SERCA:

Sarcoplasmic/endoplasmic reticulum calcium ATPase

SREBP:

Sterol regulatory element binding protein

TCA:

Tricarboxylic acid cycle

TCGA:

The cancer genome atlas

TNBC:

Triple-negative breast cancer

TRAF2:

TNF-receptor-associated factor 2

uORF:

Upstream open reading frame

UPR:

Unfolded protein response

UPRE:

Unfolded protein response element

VHL:

von Hippel-Lindau

XBP1:

X-box binding protein 1

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Acknowledgements

This work was supported by the National Cancer Institute (NCI) (1R37CA228304-01 and 5P50CA186784-03 SPORE Career Development Award to X. C.), Cancer Prevention and Research Institutes of Texas (CPRIT) (RR150009 to X. C.), and Susan G. Komen for the Cure (CCR16380871 to X. C.). The authors declare no potential conflicts of interest. The authors apologize to those whose work could not be cited owing to space limitations.

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  1. Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA

    Na Zhao, Fanglue Peng & Xi Chen

  2. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA

    Na Zhao, Fanglue Peng & Xi Chen

  3. Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA

    Na Zhao, Fanglue Peng & Xi Chen

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  1. Na Zhao
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  1. Department of Oncology, Georgetown University Medical Center, Washington, DC, USA

    Robert Clarke

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Zhao, N., Peng, F., Chen, X. (2019). The Unfolded Protein Response in Triple-Negative Breast Cancer. In: Clarke, R. (eds) The Unfolded Protein Response in Cancer. Cancer Drug Discovery and Development. Humana Press, Cham. https://doi.org/10.1007/978-3-030-05067-2_7

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