Tamoxifen resistance alters sensitivity to 5-fluorouracil in a subset of estrogen receptor-positive breast cancer.
Animals
Antimetabolites, Antineoplastic
/ pharmacology
Antineoplastic Agents, Hormonal
/ pharmacology
Apoptosis
/ drug effects
Breast Neoplasms
/ drug therapy
Capecitabine
/ pharmacology
Cell Line, Tumor
Cell Proliferation
/ drug effects
Drug Resistance, Neoplasm
/ drug effects
Estradiol
/ pharmacology
Estrogens
/ pharmacology
Female
Fluorouracil
/ pharmacology
Humans
MCF-7 Cells
Mice, Inbred BALB C
Mice, Nude
Receptors, Estrogen
/ metabolism
Tamoxifen
/ pharmacology
Xenograft Model Antitumor Assays
/ methods
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
01
02
2021
accepted:
23
05
2021
entrez:
8
6
2021
pubmed:
9
6
2021
medline:
16
11
2021
Statut:
epublish
Résumé
Sequential treatment with endocrine or chemotherapy is generally used in the treatment of estrogen receptor (ER)-positive recurrent breast cancer. To date, few studies have investigated the effect of long-term endocrine therapy on the response to subsequent chemotherapy in ER-positive breast cancer. We examined whether a preceding endocrine therapy affects the sensitivity to subsequent chemotherapy in ER-positive breast cancer cells. Three ER-positive breast cancer cell lines (T47D, MCF7, BT474) and tamoxifen-resistant sublines (T47D/T, MCF7/T, BT474/T) were analyzed for sensitivity to 5-fluorouracil, paclitaxel, and doxorubicin. The mRNA levels of factors related to drug sensitivity were analyzed by RT-PCR. MCF7/T cells became more sensitive to 5-fluorouracil than wild-type (wt)-MCF7 cells. In addition, the apoptosis induced by 5-fluorouracil was significantly increased in MCF7/T cells. However, no difference in sensitivity to chemotherapeutic agents was observed in T47D/T and BT474/T cells compared with their wt cells. Dihydropyrimidine dehydrogenase (DPYD) mRNA expression was significantly decreased in MCF7/T cells compared with wt-MCF7 cells. The expression of DPYD mRNA was restored with 5-azacytidine treatment in MCF7/T cells. In addition, DPYD 3'-UTR luciferase activity was significantly reduced in MCF7/T cells. These data indicated that the expression of DPYD mRNA was repressed by methylation of the DPYD promoter region and post-transcriptional regulation by miRNA in MCF7/T cells. In the mouse xenograft model, capecitabine significantly reduced the tumor volume in MCF7/T compared with MCF7. The results of this study indicate that endocrine therapy could alter the sensitivity to chemotherapeutic agents in a subset of breast cancers, and 5-fluorouracil may be effective in tamoxifen-resistant breast cancers.
Identifiants
pubmed: 34101751
doi: 10.1371/journal.pone.0252822
pii: PONE-D-21-03437
pmc: PMC8186817
doi:
Substances chimiques
Antimetabolites, Antineoplastic
0
Antineoplastic Agents, Hormonal
0
Estrogens
0
Receptors, Estrogen
0
Tamoxifen
094ZI81Y45
Estradiol
4TI98Z838E
Capecitabine
6804DJ8Z9U
Fluorouracil
U3P01618RT
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0252822Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
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