scholarly journals Cholesterol and Mevalonate: Two Metabolites Involved in Breast Cancer Progression and Drug Resistance through the ERRα Pathway

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1819 ◽  
Author(s):  
Matteo Brindisi ◽  
Marco Fiorillo ◽  
Luca Frattaruolo ◽  
Federica Sotgia ◽  
Michael P. Lisanti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Breast Cancer Progression ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Metabolic Switching ◽  
Breast Cancer Model ◽  
Tamr Cell

Breast cancer is the second greatest cause of cancer-related death in women. Resistance to endocrine treatments or chemotherapy is a limiting drawback. In this context, this work aims to evaluate the effects of cholesterol and mevalonate during tumor progression and their contribution in the onset of resistance to clinical treatments in use today. In this study, we demonstrated that cholesterol and mevalonate treatments were able to activate the estrogen-related receptor alpha (ERRα) pathway, increasing the expression levels of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), ERbB2/human epithelial receptor (HER2), tumor protein D52 (TPD52), and NOTCH2 proteins in breast cancer cells. The activation of this pathway is shown to be responsible for intense metabolic switching, higher proliferation rates, sustained motility, the propagation of cancer stem-like cells (CSCs), and lipid droplet formation. All of these events are related to greater tumor propagation, aggressiveness, and drug resistance. Furthermore, the activation and expression of proteins induced by the treatment with cholesterol or mevalonate are consistent with those obtained from the MCF-7/TAMr cell line, which is largely used as a breast cancer model of acquired endocrine therapy resistance. Altogether, our data indicate that cholesterol and mevalonate are two metabolites implicated in breast cancer progression, aggressiveness, and drug resistance, through the activation of the ERRα pathway. Our findings enable us to identify the ERRα receptor as a poor prognostic marker in patients with breast carcinoma, suggesting the correlation between cholesterol/mevalonate and ERRα as a new possible target in breast cancer treatment.

scholarly journals PPARgamma: A Potential Intrinsic and Extrinsic Molecular Target for Breast Cancer Therapy

Biomedicines ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 543
Author(s):  
Giuseppina Augimeri ◽  
Daniela Bonofiglio
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Patients ◽  
Cancer Progression ◽  
Regulatory Networks ◽  
Tumor Biology ◽  
Peroxisome Proliferator ◽  
Breast Cancer Patients ◽  
Peroxisome Proliferator Activated Receptor ◽  
Extracellular Matrix Components

Over the last decades, the breast tumor microenvironment (TME) has been increasingly recognized as a key player in tumor development and progression and as a promising prognostic and therapeutic target for breast cancer patients. The breast TME, representing a complex network of cellular signaling—deriving from different stromal cell types as well as extracellular matrix components, extracellular vesicles, and soluble growth factors—establishes a crosstalk with cancer cells sustaining tumor progression. A significant emphasis derives from the tumor surrounding inflammation responsible for the failure of the immune system to effectively restrain breast cancer growth. Thus, effective therapeutic strategies require a deeper understanding of the interplay between tumor and stroma, aimed at targeting both the intrinsic neoplastic cells and the extrinsic surrounding stroma. In this scenario, peroxisome proliferator-activated receptor (PPAR) γ, primarily known as a metabolic regulator, emerged as a potential target for breast cancer treatment since it functions in breast cancer cells and several components of the breast TME. In particular, the activation of PPARγ by natural and synthetic ligands inhibits breast cancer cell growth, motility, and invasiveness. Moreover, activated PPARγ may educate altered stromal cells, counteracting the pro-inflammatory milieu that drive breast cancer progression. Interestingly, using Kaplan–Meier survival curves, PPARγ also emerges as a prognostically favorable factor in breast cancer patients. In this perspective, we briefly discuss the mechanisms by which PPARγ is implicated in tumor biology as well as in the complex regulatory networks within the breast TME. This may help to profile approaches that provide a simultaneous inhibition of epithelial cells and TME components, offering a more efficient way to treat breast cancer.

scholarly journals Ly6E/K Signaling to TGFβ Promotes Breast Cancer Progression, Immune Escape, and Drug Resistance

2016 ◽  
Vol 76 (11) ◽  
pp. 3376-3386 ◽  
Author(s):  
Midrar AlHossiny ◽  
Linlin Luo ◽  
William R. Frazier ◽  
Noriko Steiner ◽  
Yuriy Gusev ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Immune Escape ◽  
Breast Cancer Progression

scholarly journals Analysis of different HER ‐2 mutations in breast cancer progression and drug resistance

2015 ◽  
Vol 19 (12) ◽  
pp. 2691-2701 ◽  
Author(s):  
Zijia Sun ◽  
Yaqin Shi ◽  
Yan Shen ◽  
Lulu Cao ◽  
Wenwen Zhang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Progression ◽  
Breast Cancer Progression ◽  
Her 2

scholarly journals Parvin-β Inhibits Breast Cancer Tumorigenicity and Promotes CDK9-Mediated Peroxisome Proliferator-Activated Receptor Gamma 1 Phosphorylation

2007 ◽  
Vol 28 (2) ◽  
pp. 687-704 ◽  
Author(s):  
Cameron N. Johnstone ◽  
Perry S. Mongroo ◽  
A. Sophie Rich ◽  
Michael Schupp ◽  
Mark J. Bowser ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Breast Cancer Cells ◽  
Three Dimensional ◽  
Nuclear Hormone Receptor ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor

ABSTRACT Parvin-β is a focal adhesion protein downregulated in human breast cancer cells. Loss of Parvin-β contributes to increased integrin-linked kinase activity, cell-matrix adhesion, and invasion through the extracellular matrix in vitro. The effect of ectopic Parvin-β expression on the transcriptional profile of MDA-MB-231 breast cancer cells, which normally do not express Parvin-β, was evaluated. Particular emphasis was placed upon propagating MDA-MB-231 breast cancer cells in three-dimensional culture matrices. Interestingly, Parvin-β reexpression in MDA-MB-231 cells increased the mRNA expression, serine 82 phosphorylation (mediated by CDK9), and activity of the nuclear hormone receptor peroxisome proliferator-activated receptor gamma (PPARγ), and there was a concomitant increase in lipogenic gene expression as a downstream effector of PPARγ. Importantly, Parvin-β suppressed breast cancer growth in vivo, with associated decreased proliferation. These data suggest that Parvin-β might influence breast cancer progression.

scholarly journals Drug-resistant cancer cell-derived exosomal EphA2 promotes breast cancer metastasis via the EphA2-Ephrin A1 reverse signaling

2021 ◽  
Vol 12 (5) ◽  
Author(s):  
Zicong Gao ◽  
Xingxing Han ◽  
Yuying Zhu ◽  
He Zhang ◽  
Ran Tian ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Drug Resistance ◽  
Cancer Cells ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Resistant Cell ◽  
Breast Cancer Progression ◽  
Drug Resistant ◽  
Drug Resistant Cell ◽  
Resistant Cells

AbstractTumor metastasis induced by drug resistance is a major challenge in successful cancer treatment. Nevertheless, the mechanisms underlying the pro-invasive and metastatic ability of drug resistance remain elusive. Exosome-mediated intercellular communications between cancer cells and stromal cells in tumor microenvironment are required for cancer initiation and progression. Recent reports have shown that communications between cancer cells also promote tumor aggression. However, little attention has been regarded on this aspect. Herein, we demonstrated that drug-resistant cell-derived exosomes promoted the invasion of sensitive breast cancer cells. Quantitative proteomic analysis showed that EphA2 was rich in exosomes from drug-resistant cells. Exosomal EphA2 conferred the invasive/metastatic phenotype transfer from drug-resistant cells to sensitive cells. Moreover, exosomal EphA2 activated ERK1/2 signaling through the ligand Ephrin A1-dependent reverse pathway rather than the forward pathway, thereby promoting breast cancer progression. Our findings indicate the key functional role of exosomal EphA2 in the transmission of aggressive phenotype between cancer cells that do not rely on direct cell–cell contact. Our study also suggests that the increase of EphA2 in drug-resistant cell-derived exosomes may be an important mechanism of chemotherapy/drug resistance-induced breast cancer progression.

Abstract 1582: Identification of BCAR genes relevant for breast cancer progression and endocrine therapy resistance

2008 ◽  
Author(s):  
Ton Van Agthoven ◽  
Jos Veldscholte ◽  
Anieta Sieuwerts ◽  
Marcel Smid ◽  
Marion E Meijer-Van Gelder ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Endocrine Therapy ◽  
Cancer Progression ◽  
Therapy Resistance ◽  
Breast Cancer Progression ◽  
Endocrine Therapy Resistance
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