Reduced Expression of miR-200 Family Members Contributes to Antiestrogen Resistance in LY2 Human Breast Cancer Cells

Autor: Numan Al-Rayyan, Carolyn M. Klinge, Penn Muluhngwi, Tissa T. Manavalan, Lacey M. Litchfield, Yun Teng
Jazyk: angličtina
Rok vydání: 2013
Předmět:
Tumor Physiology
Cancer Treatment
Estrogen receptor
lcsh:Medicine
Gene Expression
Cell morphology
Biochemistry
Epigenesis
Genetic
0302 clinical medicine
RNA interference
Molecular cell biology
Endocrinology
Cell Movement
Basic Cancer Research
Breast Tumors
lcsh:Science
0303 health sciences
Multidisciplinary
Estradiol
Cancer Risk Factors
Cadherins
Gene Expression Regulation
Neoplastic
Oncology
030220 oncology & carcinogenesis
Gene Knockdown Techniques
MCF-7 Cells
Medicine
Epigenetics
Female
medicine.drug
Research Article
medicine.medical_specialty
Epithelial-Mesenchymal Transition
Antineoplastic Agents
Hormonal
Breast Neoplasms
Biology
Epigenetic Therapy
03 medical and health sciences
Internal medicine
Cell Line
Tumor
medicine
Genetics
Cancer Genetics
Humans
Epithelial–mesenchymal transition
030304 developmental biology
Homeodomain Proteins
Fulvestrant
Endocrine Physiology
Cell growth
lcsh:R
Cancers and Neoplasms
Zinc Finger E-box-Binding Homeobox 1
Chemotherapy and Drug Treatment
Antiestrogen
Hormones
MicroRNAs
Trichostatin A
Drug Resistance
Neoplasm
Cancer cell
Cancer research
lcsh:Q
Hydroxytestosterones
Transcription Factors
Zdroj: PLoS ONE
PLoS ONE, Vol 8, Iss 4, p e62334 (2013)
ISSN: 1932-6203
Popis: Introduction The role of miRNAs in acquired endocrine-resistant breast cancer is not fully understood. One hallmark of tumor progression is epithelial-to-mesenchymal transition (EMT), characterized by a loss of cell adhesion resulting from reduced E-cadherin and increased cell mobility. miR-200 family members regulate EMT by suppressing expression of transcriptional repressors ZEB1/2. Previously we reported that the expression of miR-200a, miR-200b, and miR-200c was lower in LY2 endocrine-resistant, mesenchymal breast cancer cells compared to parental, endocrine sensitive, epithelial MCF-7 breast cancer cells. Here we investigated the regulation of miR-200 family members and their role in endocrine-sensitivity in breast cancer cells. Results miR-200 family expression was progressively reduced in a breast cancer cell line model of advancing endocrine/tamoxifen (TAM) resistance. Concomitant with miR-200 decrease, there was an increase in ZEB1 mRNA expression. Overexpression of miR-200b or miR-200c in LY2 cells altered cell morphology to a more epithelial appearance and inhibited cell migration. Further, miR-200b and miR-200c overexpression sensitized LY2 cells to growth inhibition by estrogen receptor (ER) antagonists TAM and fulvestrant. Knockdown of ZEB1 in LY2 cells recapitulated the effect of miR-200b and miR-200c overexpression resulting in inhibition of LY2 cell proliferation by TAM and fulvestrant, but not the aromatase inhibitor exemestane. Demethylating agent 5-aza-2′-deoxycytidine (5-aza-dC) in combination with histone deacetylase inhibitor trichostatin A (TSA) increased miR-200b and miR-200c in LY2 cells. Concomitant with the increase in miR-200b and miR-200c, ZEB1 expression was decreased and cells appeared more epithelial in morphology and were sensitized to TAM and fulvestrant inhibition. Likewise, knockdown of ZEB1 increased antiestrogen sensitivity of LY2 cells resulting in inhibition of cell proliferation. Conclusions Our data indicate that reduced miRNA-200b and miR-200c expression contributes to endocrine resistance in breast cancer cells and that the reduced expression of these miR-200 family members in endocrine-resistant cells can be reversed by 5-aza-dC+TSA.
Databáze: OpenAIRE
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