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

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.

SUBMITTER: Fang WB

PROVIDER: S-EPMC4456035 | biostudies-literature | 2015 Apr

REPOSITORIES: biostudies-literature

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

Fang Wei Bin WB Yao Min M Jokar Iman I Alhakamy Nabil N Berkland Cory C Chen Jin J Brantley-Sieders Dana D Cheng Nikki N

Breast cancer research and treatment 20150306 2

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 lumi ...[more]

PMID: 25744294

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Project description:Chronic inflammation associated with cancer is characterized by the production of different types of chemokines and cytokines. In cancer, numerous signaling pathways upregulate the expression levels of several cytokines and evolve cells to the neoplastic state. Therefore, targeting these signaling pathways through the inhibition of distinctive gene expression is a primary target for cancer therapy. The present study investigated the anticancer effects of the natural polyphenol gossypol (GOSS) in triple‑negative breast cancer (TNBC) cells, the most aggressive breast cancer type with poor prognosis. GOSS effects were examined in two TNBC cell lines: MDA‑MB‑231 (MM‑231) and MDA‑MB‑468 (MM‑468), representing Caucasian Americans (CA) and African Americans (AA), respectively. The obtained IC50s revealed no significant difference between the two cell lines' response to the compound. However, the use of microarray assays for cytokine determination indicated the ability of GOSS to attenuate the expression levels of cancer‑related cytokines in the two cell lines. Although GOSS did not alter CCL2 expression in MM‑468 cells, it was able to cause 30% inhibition in TNF‑α‑stimulated MM‑231 cells. Additionally, IL‑8 was not altered by GOSS treatment in MM‑231 cells, while its expression was inhibited by 60% in TNF‑α‑activated MM‑468 cells. ELISA assays supported the microarray data and indicated that CCL2 expression was inhibited by 40% in MM‑231 cells, and IL‑8 expression was inhibited by 50% in MM‑468 cells. Furthermore, in MM‑231 cells, GOSS inhibited CCL2 release via the repression of IKBKE, CCL2 and MAPK1 gene expression. Additionally, in MM‑468 cells, the compound downregulated the release of IL‑8 through repressing IL‑8, MAPK1, MAPK3, CCDC88A, STAT3 and PIK3CD gene expression. In conclusion, the data obtained in the present study indicate that the polyphenol compound GOSS may provide a valuable tool in TNBC therapy.

Dataset Information

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

Publications

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

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