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The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells

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Abstract

Luminal A and B breast cancers are the most prevalent forms of breast cancer diagnosed in women. Compared to luminal A breast cancer patients, patients with luminal B breast cancers experience increased disease recurrence and lower overall survival. The mechanisms that regulate the luminal B subtype remain poorly understood. The chemokine CCL2 is overexpressed in breast cancer, correlating with poor patient prognosis. The purpose of this study was to determine the role of CCL2 expression in luminal B breast cancer cells. Breast tissues, MMTV-PyVmT and MMTV-Neu transgenic mammary tumors forming luminal B-like lesions, were immunostained for CCL2 expression. To determine the role of CCL2 in breast cancer cells, CCL2 gene expression was silenced in mammary tumor tissues and cells using TAT cell-penetrating peptides non-covalently cross linked to siRNAs (Ca-TAT/siRNA). CCL2 expression was examined by ELISA and flow cytometry. Cell growth and survival were analyzed by flow cytometry, immunocytochemistry, and fluorescence microscopy. CCL2 expression was significantly increased in luminal B breast tumors, MMTV- PyVmT and MMTV-Neu mammary tumors, compared or normal breast tissue or luminal A breast tumors. Ca-TAT delivery of CCL2 siRNAs significantly reduced CCL2 expression in PyVmT mammary tumors, and decreased cell proliferation and survival. CCL2 gene silencing in PyVmT carcinoma cells or BT474 luminal B breast cancer cells decreased cell growth and viability associated with increased necrosis and autophagy. CCL2 expression is overexpressed in luminal B breast cancer cells and is important for regulating cell growth and survival by inhibiting necrosis and autophagy.

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Abbreviations

Ca-TAT:

Calcium crosslinked TAT

CCL2:

Chemokine (C–C motif) ligand 2

siRNA:

Small interfering RNA

MMTV:

Mouse mammary tumor virus

PyVmT:

Polyoma virus middle T

HMGB1:

High mobility group box 1

LC3B:

Light chain 3B

TNF-a:

Tumor necrosis alpha

TRAIL:

TNF-related apoptosis inducing ligand

RIPK:

Receptor interacting protein kinase

FBS:

Fetal bovine serum

BSA:

Bovine serum albumin

NBF:

Neutral formalin buffer

SEM:

Standard error of the mean

ANOVA:

Analysis of variance

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Acknowledgments

This work was supported by grants from: the KUCC Pilot Grants Program, Kansas Bioscience Authority, NIH/NCI (CA127357) and American Cancer Society (RSG-13-182-01-CSM).

Conflict of interest

C. Berkland has a patent (US 20110287547 A1) on Ca-TAT peptides. These studies were not solicited or funded by any pharmaceutical company.

Ethical standards

The authors declare that the experiments comply with the current laws of the country in which they were performed.

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Correspondence to Nikki Cheng.

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Fang, W.B., Yao, M., Jokar, I. et al. The CCL2 chemokine is a negative regulator of autophagy and necrosis in luminal B breast cancer cells. Breast Cancer Res Treat 150, 309–320 (2015). https://doi.org/10.1007/s10549-015-3324-4

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