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TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF?7 cells.

ABSTRACT: Tamoxifen is widely used as a highly effective drug for treating estrogen?receptor (ER) alpha?positive breast cancer. However, tamoxifen resistance developed during cancer treatment remains a significant challenge. Tongue cancer resistance?related protein1 (TCRP1), which is recognized as a novel drug target, is related to chemo?resistance in human cancers, moreover, it is often overexpressed in various cancer cells, such as in lung cancer, breast cancer, and tongue cancer. However, the effects of TCRP1 on tamoxifen?resistant breast cancer cells and tissues are far from clear. The present study revealed that TCRP1 induced tamoxifen resistance in breast cancer cells. Western blotting, quantitative real?time polymerase chain reaction (RT?PCR) and immunohistochemical staining were performed to detect the expression level of TCRP1 in vivo and in vitro between primary breast cancer tissues and tamoxifen?resistant breast cancer tissues. The data revealed that the expression of TCRP1 was upregulated in the tamoxifen?resistant breast cancer tissues and human breast cancer cell line, MCF?7. Further study revealed that knocking down TCRP1 inhibited the growth of MCF?7 cells with tamoxifen?resistance (MCF7?R cells) and induced cell apoptosis. Moreover, TCRP1 promoted serum? and glucocorticoid?inducible kinase 1 (SGK1) activation via phosphorylation of phosphoinositide?dependent kinase 1 (PDK1) in MCF7?R cells. In addition, it was also observed that knocking down TCRP1 inhibited tumorigenesis of MCF?7 cells in nude mice. In conclusion, these data indicated that TCRP1 could induce tamoxifen resistance by regulating the PDK1/SGK1 signaling pathway. Thus, TCRP1 could be explored as a promising candidate for treating tamoxifen?resistant breast cancer in the future.

SUBMITTER: Zhao S

PROVIDER: S-EPMC7160545 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF‑7 cells.

Zhao Shuai S Li Xiaohua X Yin Lei L Hou Lili L Lan Jing J Zhu Xun X

Oncology reports 20200403 6

Tamoxifen is widely used as a highly effective drug for treating estrogen‑receptor (ER) alpha‑positive breast cancer. However, tamoxifen resistance developed during cancer treatment remains a significant challenge. Tongue cancer resistance‑related protein1 (TCRP1), which is recognized as a novel drug target, is related to chemo‑resistance in human cancers, moreover, it is often overexpressed in various cancer cells, such as in lung cancer, breast cancer, and tongue cancer. However, the effects o ...[more]

PMID: 32323833

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Project description:BackgroundTamoxifen (TAM) is the eminent first-line drug for endocrine therapy of hormone receptor positive premenopausal breast cancer and reduces the risk of recurrence by ∼50%. However, many patients developed TAM resistance and their diseases recurred. Our previous study on transcriptome profile of TAM resistant breast cancer cells revealed that the TMEM47 is one of the most significantly differentially expressed genes. The mechanism of how TMEM47 is involved in TAM resistance was not known.MethodsWe constructed a mammal breast cancer cell line, in which TMEM47 was stably overexpressed (TMEM47-OE/MCF-7), to further verify the role of TMEM47 in TAM resistance. siRNA targeting TMEM47 was transfected into TAMR / MCF-7 cells by Liposome. TMEM47 expression was validated on mRNA and protein level by qRT-PCR and western blotting. We tested the cytotoxicity of TAM in the cells. Apoptosis was detected by flow cytometry.ResultsCompared to the MCF7 cells, TMEM47 mRNA was significantly up regulated more than 6 folds in the TAMR/MCF7 cells and so its protein. TMEM47 expression level in TMEM47-OE/MCF-7 was similar as in the TAMR/MCF-7 cells. The 50% inhibitory concentration (IC50) value (mean ± SD) of TAM in MCF-7, TAMR/MCF-7 and TMEM47-OE/MCF-7 cells was 1.58 ± 0.19, 2.74 ± 0.24 and 3.12 ± 0.32 µγ/mL, respectively. The apoptosis rates of TAMR/MCF-7 and TMEM47-OE/MCF-7 cell lines were significantly lower than that of MCF-7 cells. After 24 and 48 hours TAM treatments, cell viability was significantly inhibitied in TMEM47 knockdown TAMR/MCF7 cells (P < 0.01). Consistant with the decreased cell viability, the apoptosis rate in TMEM47 knockdown TAMR/MCF-7 cells was significantly increased.ConclusionsOur results suggest that overexpression of TMEM47 in MCF-7 cells acquired TAM resistance to those cells, and knockdown of TMEM47 in TAMR/MCF-7 cells reversed their resistance to TAM. TMEM47 might confer TAM resistance on MCF-7 cells through the inhibition of apoptosis.

Project description:IntroductionAcquired tamoxifen resistance involves complex signaling events that are not yet fully understood. Successful therapeutic intervention to delay the onset of hormone resistance depends critically on mechanistic elucidation of viable molecular targets associated with hormone resistance. This study was undertaken to investigate the global proteomic alterations in a tamoxifen resistant MCF-7 breast cancer cell line obtained by long term treatment of the wild type MCF-7 cell line with 4-hydroxytamoxifen (4-OH Tam).MethodsWe cultured MCF-7 cells with 4-OH Tam over a period of 12 months to obtain the resistant cell line. A gel-free, quantitative proteomic method was used to identify and quantify the proteome of the resistant cell line. Nano-flow high-performance liquid chromatography coupled to high resolution Fourier transform mass spectrometry was used to analyze fractionated peptide mixtures that were isobarically labeled from the resistant and control cell lysates. Real time quantitative PCR and Western blots were used to verify selected proteomic changes. Lentiviral vector transduction was used to generate MCF-7 cells stably expressing S100P. Online pathway analysis was performed to assess proteomic signatures in tamoxifen resistance. Survival analysis was done to evaluate clinical relevance of altered proteomic expressions.ResultsQuantitative proteomic analysis revealed a wide breadth of signaling events during transition to acquired tamoxifen resistance. A total of 629 proteins were found significantly changed with 364 up-regulated and 265 down-regulated. Collectively, these changes demonstrated the suppressed state of estrogen receptor (ER) and ER-regulated genes, activated survival signaling and increased migratory capacity of the resistant cell line. The protein S100P was found to play a critical role in conferring tamoxifen resistance and enhanced cell motility.ConclusionsOur data demonstrate that the adaptive changes in the proteome of tamoxifen resistant breast cancer cells are characterized by down-regulated ER signaling, activation of alternative survival pathways, and enhanced cell motility through regulation of the actin cytoskeleton dynamics. Evidence also emerged that S100P mediates acquired tamoxifen resistance and migration capacity.

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TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF?7 cells.

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TCRP1 induces tamoxifen resistance by promoting the activation of SGK1 in MCF‑7 cells.

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