ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM

Zhang, Xiang; Zhang, Zhen; Zhang, Qing; Zhang, Quansheng; Sun, Peiqing; Xiang, Rong; Ren, Guosheng; Yang, Shuang

doi:10.1038/s41419-017-0087-3

Cited by 92 publications

(77 citation statements)

References 62 publications

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“…No significant influence of RA on the mRNA level was found for the ABCB1, TWIST1 and PTEN genes as compared to the control MCF-7 cells. sion of ZEB1 has been observed in many cancer types and is considered to be associated with poor prognosis in some cancers (breast, ovarian, lung and pancreatic) [18][19][20][21]. The protein encoded by ZEB1 has been identified as the key factor in BC differentiation and metastasis regulation.…”

Section: Resultsmentioning

confidence: 99%

“…The protein encoded by ZEB1 has been identified as the key factor in BC differentiation and metastasis regulation. Patients with various tumors, including breast cancer, demonstrating high ZEB1 expression responded poorly to chemotherapy [21]. In another study, a positive correlation between human telomerase reverse transcriptase (hTERT) and ZEB1 expression in breast cancer was discovered, which indicates that this gene controls cancer cell proliferation and apoptosis [17].…”

Section: Resultsmentioning

confidence: 99%

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Expression profiling of genes modulated by rosmarinic acid (RA) in MCF-7 breast cancer cells

et al. 2018

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Objectives: Cancer is the second most common cause of death, with breast cancer (BC) as the most frequently diagnosed neoplasm among females. The origin of BC is multifactorial and depends on environmental and genetic factors. The disease presents a significant challenge due to its drug resistance and frequent metastasis. Thus, new effective therapies and metastasis prevention are much needed. Rosmarinic acid (RA) is a natural polyphenol which possesses the ability to inhibit BC cell proliferation and demonstrates cytotoxic properties against those cells. In our study, we examined the effect of RA on the expression of ZEB1, MDM2, ABCB1, PTEN and TWIST1 genes in MCF-7 breast cancer cells. Material and methods: MCF-7 cell cultures were treated with 0.2 µM doxorubicin (DOX) and 1.5, 15 or 50 µM of RA. Real-time PCR reaction was performed to analyze gene expression levels. Results: PCR analysis showed a significant increase of the ZEB1 gene expression, which was about 3-fold for DOX 0.2 µM, 9-fold for 0.2 µM DOX + 1.5 µM RA and 0.2 µM DOX + 15 µM RA (p < 0.05), and about 6.5-fold for 0.2 µM DOX + 50 µM RA (p < 0.05). Furthermore, a decrease of the MDM2 gene expression was observed in all of the examined variants and was about 40-75% (p < 0.05). No influence of DOX and RA combined with DOX on the ABCB1, TWIST1 and PTEN genes was found. Conclusions: The results of our study suggest that RA might be used as an adjuvant therapeutic factor in BC treatment.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Expression profiling of genes modulated by rosmarinic acid (RA) in MCF-7 breast cancer cells

et al. 2018

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“…A recent study reported that ZEB1 conferred chemotherapeutic resistance to breast cancer and SLC3A2 is a target gene of ZEB1 in breast cancer chemoresistance [15]. Thus, we investigated the role of SLC3A2 and the interaction between ZEB1 and SLC3A2 in the regulation of cisplatin-resistance in ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

“…Zhang et al [15] recently reported that ZEB1 conferred chemotherapeutic resistance in breast cancer and identified that SLC3A2 (CD98hc) was a target gene of ZEB1 in breast cancer chemoresistance, suggesting the possible interaction between ZEB1 and SLC3A2. SLC3A2 is a type II transmembrane cell surface molecule.…”

Section: Introductionmentioning

confidence: 99%

ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2

et al. 2018

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Ovarian cancer is one of the deadliest gynecological malignancies in women. Chemoresistance has been a major obstacle for ovarian cancer treatment. Zinc finger E-box-binding homeobox 1 (ZEB1) is an important regulator of tumor development in various types of cancer. Abnormal expression of SLC3A2 (CD98hc), a type 2 transmembrane cell surface molecule, has been described in several cancers. This study was designed to investigate the role of ZEB1 and SLC3A2 in the chemoresistance to cisplatin in ovarian cancer cells. We found that ZEB1 was increased in cisplatin-resistant SKOV3/DPP cells. Downregulation of ZEB1 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. In addition, downregulation of ZEB1 decreased the volume and weight of implanted tumors. SLC3A2 was decreased in cisplatin-resistant SKOV3/DPP cells. Upregulation of SLC3A2 significantly decreased cell viability in response to cisplatin, increased cisplatin-induced apoptosis, and decreased migration and invasion in the presence of cisplatin. Moreover, upregulation of SLC3A2 decreased the volume and weight of implanted tumors. Downregulation of ZEB1 resulted in a significant increase of SLC3A2 expression. Moreover, downregulation of SLC3A2 significantly inhibited ZEB1 knockdown-mediated inhibition of cisplatin-resistance. ZEB1-mediated regulation of SLC3A2 was involved in the chemoresistance to cisplatin in ovarian cancer cells. Overall, we provide new insights into the mechanism of chemoresistance to cisplatin in ovarian cancer cells. ZEB1/SLC3A2 may be promising therapeutic targets for enhancement of the sensitivity of ovarian cancer cells to cisplatin-mediated chemotherapy.

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“…ZEB1 is known in the scientific community to play a role in tumorigenicity. Studies have shown that it is also linked to chemoresistance in breast cancer (Zhang 2018). Breast cancer is closely linked to ovarian cancer when considering genetics.…”

Section: Discussionmentioning

confidence: 99%

The Cancer Stem Cell Marker GSK3b, a Gene involved in Oxidative Stress, Modulates Chemoresistance in Ovarian Cancer

Cutter¹,

Fiederlein²,

McNulty³

et al. 2019

JALS

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The leading cause of death from gynecologic malignancies is epithelial ovarian cancer. These tumors are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumors in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumor relapse. While chemotherapy is the preferred treatment modality, chemoresistance severely limits treatment success. It has been hypothesized that cancer stem cells are at the root of this problem. Their ability to self-renew and proliferate is what causes a large number of ovarian cancers to recur and not respond to normal chemotherapeutic treatments. Recent evidence suggests that deregulation of stem cell pathways is a key factor in the onset and maintenance of chemoresistance. Several key markers such as BMI1, FZD1, GGSK3b, NANOG, TWIST1, and OCT4 (POU5F1) are hypothesized to play a central role in the development and differentiation of multiple cell lineages. Recent studies have demonstrated that these markers is required for the carcinogenesis in several cancer types. The aim of this study was to investigate the significance of CSC expression in chemoresistant and sensitive ovarian cancer cancer cell lines. Through the analysis of gene expression in these cell lines, CSC markers could be identified. CSC mRNA expression was detected by real-time quantitative PCR and by gel electrophoresis of PCR products in sensitive and resistant ovarian cell lines. The objective of such an improved delineation is to develop targeted therapy for selective elimination of cancer stem cells with minimal toxicity to normal stem cells. Our research indicates that there were novel changes in gene expression in the chemoresistant cell lines, specifically involving GSK3b. Further research is needed to gain better understanding of the role that these genes specifically play in cancer survival, metastasis, and chemo resistance.

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ZEB1 confers chemotherapeutic resistance to breast cancer by activating ATM

Cited by 92 publications

References 62 publications

Expression profiling of genes modulated by rosmarinic acid (RA) in MCF-7 breast cancer cells

Expression profiling of genes modulated by rosmarinic acid (RA) in MCF-7 breast cancer cells

ZEB1 Promotes Chemoresistance to Cisplatin in Ovarian Cancer Cells by Suppressing SLC3A2

The Cancer Stem Cell Marker GSK3b, a Gene involved in Oxidative Stress, Modulates Chemoresistance in Ovarian Cancer

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