COMPARATIVE ANALYSIS OF THE EXOSOMAL CARGO OF THE ESTROGEN-RESISTANT BREAST CANCER CELLS

The exosomes involvement in the pathogenesis of tumors is based on their property to incorporate into the recipient cells resulting in the both genomic and epigenomic changes. Earlier we have shown that exosomes from different types of estrogen-independent breast cancer cells (MCF-7/T developed by long-term tamoxifen treatment, and MCF-7/M) developed by metformin treatment were able to transfer resistance to the parent MCF-7 cells. To elucidate the common features of the both types of resistant exosomes, the proteome and microRNA cargo of the control and both types of the resistant exosomes were analyzed. Totally, more than 400 proteins were identified in the exosome samples. Of these proteins, only two proteins, DMBT1 (Deleted in Malignant Brain Tumors 1) and THBS1 (Thrombospondin-1), were commonly expressed in the both resistant exosomes (less than 5% from total DEPs) demonstrating the unique protein composition of each type of the resistant exosomes. The comparative analysis of the miRNA differentially expressed in the both MCF-7/T and MCF-7/M resistant exosomes revealed 180 up-regulated and 202 down-regulated miRNAs. Among them, 4 up-regulated and 8 down-regulated miRNAs were associated with progression of hormonal resistance of breast tumors. The bioinformatical analysis of 4 up-regulated exosomal miRNAs revealed 2 miRNAs, mir- 101and mir-181b, which up-regulated PI3K signaling supporting the key role of PI3K/Akt in the development of the resistant phenotype of breast cancer cells.

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CURCUMIN INCREASES THE SENSITIVITY OF BREAST CANCER CELLS TO TAMOXIFEN BY INHIBITING MRP2 MRNA EXPRESSION OF EFFLUX TRANSPORTER MRP2

International Journal of Applied Pharmaceutics ◽

10.22159/ijap.2019.v11s6.33553 ◽

2019 ◽

pp. 88-90

Author(s):

DESAK GEDE BUDI KRISNAMURTI ◽

SEPTELIA INAWATI WANANDI ◽

MELVA LOUISA

Keyword(s):

Breast Cancer ◽

T Cells ◽

Cell Viability ◽

Mrna Expression ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Treatment ◽

Efflux Transporter ◽

Mcf 7

Objective: Tamoxifen is the drug of choice to treat breast cancer positive for estrogen receptor. Long-term use of tamoxifen can induce multidrug resistance (MDR) associated with decreased sensitivity of cancer cells to the drug. One of the causes of MDR is overexpression of efflux transporter multidrug resistance-associated protein (MRP)2. Various drugs are known to act as MRP2 inhibitors, including curcumin. This study investigated the effects of curcumin on the sensitivity of breast cancer cells to tamoxifen through inhibition of MRP2. Methods: We used MCF-7 cells that were previously exposed to long-term tamoxifen treatment [MCF-7(T) cells]. MCF-7(T) cells were treated with 1 µM tamoxifen, curcumin (5, 10, and 20 µM), combinations of curcumin (5, 10, and 20 µM) and 1 µM tamoxifen, or 10 µM nevirapine (a known MRP2 inhibitor) for 5 d. Then, the cells were harvested, counted to assess cell viability, and evaluated for MRP2 mRNA expression. Results: Treatment with curcumin alone or in combination with tamoxifen significantly reduced cell viability at all curcumin concentrations compared with the control. The reduction in cell viability was accompanied by a reduced level of MRP2 mRNA expression. Conclusion: Application of curcumin to MCF-7 cells previously exposed to long-term tamoxifen treatment increase the sensitivity of cancer cells to tamoxifen. The increased sensitivity of these cells was attributed, at least in part, to inhibition of the efflux transporter MRP2.

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Inhibition of GSK-3β activity can result in drug and hormonal resistance and alter sensitivity to targeted therapy in MCF-7 breast cancer cells

Cell Cycle ◽

10.4161/cc.27728 ◽

2014 ◽

Vol 13 (5) ◽

pp. 820-833 ◽

Cited By ~ 25

Author(s):

Melissa Sokolosky ◽

William H Chappell ◽

Kristin Stadelman ◽

Stephen L Abrams ◽

Nicole M Davis ◽

...

Keyword(s):

Breast Cancer ◽

Targeted Therapy ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Hormonal Resistance ◽

Gsk 3Β ◽

Mcf 7

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The role of mitochondrial estrogen receptor β in relapse of breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e12540 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e12540-e12540

Author(s):

Tae Hyun Kim ◽

In-Sung Song ◽

Jin Han

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Estrogen Receptor ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Tamoxifen Treatment ◽

Significant Difference ◽

Mcf 7

e12540 Background: Breast cancer is the most common non-skin cancer in women. Breast cancers are heterogeneous, and treatment by subgroup based on hormone receptor and HER2 made a significant difference in clinical outcomes. Several studies have reported that estrogen receptor beta (ERβ) decreases during tumor development in the breast epithelium. However, the role of ERβ in relapse and metastasis of breast cancer is poorly understood. Methods: In this study, we retrospectively studied 30 case breast carcinomas divided luminal, HER2, and triple negative subtype. Among them, patients relapsed within 5 years are 6 cases. The expression of ERβ gene in breast cancer tissues (30 cases) was estimated using a quantitative PCR, and other marker (ERα, HER2, PR etc) was measured anonymously in formalin-fixed paraffin-embedded tumor sections, by using specific antibodies. Results: A low level of ERβ expression and mitochondrial translocation of ERβ was associated with relapse/metastasis of breast cancer. The ERβ depletion resulted in resistance in response to tamoxifen treatment of MCF-7 breast cancer cells. Conversely, the overexpression of mitochondrial ERβ enhanced the cell death by treatment of tamoxifen in MCF-7 cells. We found that ERβ localizes to the mitochondria via the interaction with Grp75 and improves mitochondrial oxygen consumption rate and ATP production in breast cancer cells. Finally, we showed that ERβ level was a low in the breast cancer stem cells (CD24-CD44+ cells) compared with breast non-cancer stem cells (CD24+CD44- cells), whereas ERα level was a high. The overexpression of mitochondrial ERβ contribute to a decrease of sphere formation showing a tumorigenic ability. Conclusions: The mitochondrial ERβ contribute to suppress survival and stemness of cancer stem cells for relapse/metastasis, promising to the development of novel strategies for the treatment of breast cancer patients.

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CHANGES IN DNA METHYLATION PROFILE IN TAMOXIFEN-RESISTANT MCF-7 SUBLINES

Siberian Journal of Oncology ◽

10.21294/1814-4861-2019-18-5-45-53 ◽

2019 ◽

Vol 18 (5) ◽

pp. 45-53

Author(s):

О. Е. Andreeva ◽

V. О. Sigin ◽

V. V. Strelnikov ◽

A. S. Tanas ◽

A. M. Scherbakov ◽

...

Keyword(s):

Breast Cancer ◽

Dna Methylation ◽

Cancer Cells ◽

Breast Cancer Cells ◽

Secondary Resistance ◽

Resistant Phenotype ◽

Hormonal Resistance ◽

Mcf 7 ◽

In Cells ◽

Resistant Cells

Abstract Introduction. We have previously shown the feasibility of hormonal resistance horizontal distribution from cell to cell, with the joint cultivation of sensitive and resistant cells and/or through exosomes secreted by resistant cells. What is the mechanism of such resistance distribution, and how do cells with secondary resistance reproduce the characteristics of donor resistant cells? To answer these questions, we analyzed the overall level of DNA methylation in MCF-7 estrogen-dependent breast cancer cells and estrogen-independent sublinia.The purpose of the study was to analyze DNA methylation profiles for the development of hormonal resistance by breast cancer cells and for resistant phenotype further accession.Methods. DNA methylation was evaluated by the RRBS (Reduced Representation Bisulfite Sequencing) method in MCF-7 breast cancer cells and their resistant sublines.Results. 19 CpG dinucleotides, differentially and generally unidirectionally methylated in cells with primary and secondary resistance to tamoxifen, were detected. Differential changes in methylation were found for DNA regions that regulated the expression of six protein-coding genes: PRKCZ, TRAPPC9, AS IC2, C2CD4A, ZNF787, CRTAC 1. Bioinformatics analysis showed that two of these six genes, PRKCZ (protein kinase C Zeta) and TRAPPC9 (Trafficking Protein Particle Complex Subunit 9) were directly involved in the regulation of NF-κB activity.Conclusion. The data obtained indicate the existence of common DNA patterns, the methylation of which varies in the same direction in cells with primary and secondary resistance. The involvement of two of the identified genes in the regulation of NF-κB may indicate the inclusion of the latter in the formation of a resistant phenotype of tumor cells, even under conditions of horizontal transfer of resistance.

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