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Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation.

Wang N, Wang Z, Wang Y, Xie X, Shen J, Peng C, You J, Peng F, Tang H, Guan X, Chen J - Oncotarget (2015)

Bottom Line: In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase.Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1.Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.

ABSTRACT
Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of β-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus

ISL significantly elevated WIF1 expression in MMTV-PyMT miceA. Real-time PCR analysis revealed that ISL significantly increased WIF1 mRNA expression in mammary tumors of MMTV-PyMT mice at the end of the experiment; B–C. Western blotting and immunohistochemistry analysis further confirmed that ISL gradually increased WIF1 expression from the 4th to the 12th week.
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Figure 4: ISL significantly elevated WIF1 expression in MMTV-PyMT miceA. Real-time PCR analysis revealed that ISL significantly increased WIF1 mRNA expression in mammary tumors of MMTV-PyMT mice at the end of the experiment; B–C. Western blotting and immunohistochemistry analysis further confirmed that ISL gradually increased WIF1 expression from the 4th to the 12th week.

Mentions: To further examine the relevance of WIF1 to the chemopreventive effects of ISL, the mRNA levels of WIF1 in mammary tissues from vehicle and ISL-treated groups were examined by RT-PCR. The results revealed a significant elevation of WIF1 by ISL treatment when compared to the vehicle control (Figure 4A). In addition, western blot analysis also confirmed that ISL administration led to an increase in WIF1 expression levels as time progressed from the 4th to the 12th week (Figure 4B). Furthermore, immunohistochemistry staining showed that WIF1 was expressed in wild-type mammary tissues in mice from weanlings to adults (Figure 4C). However, WIF1 expression was significantly attenuated in MMTV-PyMT mice, particularly after tumor development. Notably, augmentation of WIF1 expression was observed in ISL-treated mammary tissues, especially when the hyperplasia had developed to the carcinoma stage at the 12th week of age. Additionally, the distribution of WIF1 positive cells at the hyperplasic stage (4–6 weeks) was quite different from that at the carcinoma stage (12 weeks); specifically, WIF1 localization changed from primarily the outer layer of lesions to being distributed throughout the entire tumor.


Dietary compound isoliquiritigenin prevents mammary carcinogenesis by inhibiting breast cancer stem cells through WIF1 demethylation.

Wang N, Wang Z, Wang Y, Xie X, Shen J, Peng C, You J, Peng F, Tang H, Guan X, Chen J - Oncotarget (2015)

ISL significantly elevated WIF1 expression in MMTV-PyMT miceA. Real-time PCR analysis revealed that ISL significantly increased WIF1 mRNA expression in mammary tumors of MMTV-PyMT mice at the end of the experiment; B–C. Western blotting and immunohistochemistry analysis further confirmed that ISL gradually increased WIF1 expression from the 4th to the 12th week.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4496402&req=5

Figure 4: ISL significantly elevated WIF1 expression in MMTV-PyMT miceA. Real-time PCR analysis revealed that ISL significantly increased WIF1 mRNA expression in mammary tumors of MMTV-PyMT mice at the end of the experiment; B–C. Western blotting and immunohistochemistry analysis further confirmed that ISL gradually increased WIF1 expression from the 4th to the 12th week.
Mentions: To further examine the relevance of WIF1 to the chemopreventive effects of ISL, the mRNA levels of WIF1 in mammary tissues from vehicle and ISL-treated groups were examined by RT-PCR. The results revealed a significant elevation of WIF1 by ISL treatment when compared to the vehicle control (Figure 4A). In addition, western blot analysis also confirmed that ISL administration led to an increase in WIF1 expression levels as time progressed from the 4th to the 12th week (Figure 4B). Furthermore, immunohistochemistry staining showed that WIF1 was expressed in wild-type mammary tissues in mice from weanlings to adults (Figure 4C). However, WIF1 expression was significantly attenuated in MMTV-PyMT mice, particularly after tumor development. Notably, augmentation of WIF1 expression was observed in ISL-treated mammary tissues, especially when the hyperplasia had developed to the carcinoma stage at the 12th week of age. Additionally, the distribution of WIF1 positive cells at the hyperplasic stage (4–6 weeks) was quite different from that at the carcinoma stage (12 weeks); specifically, WIF1 localization changed from primarily the outer layer of lesions to being distributed throughout the entire tumor.

Bottom Line: In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase.Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1.Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

View Article: PubMed Central - PubMed

Affiliation: School of Chinese Medicine, Li Ka Shing Faculty of Medicine, the University of Hong Kong, Hong Kong.

ABSTRACT
Breast cancer stem cells (CSCs) are considered as the root of mammary tumorigenesis. Previous studies have demonstrated that ISL efficiently limited the activities of breast CSCs. However, the cancer prevention activities of ISL and its precise molecular mechanisms remain largely unknown. Here, we report a novel function of ISL as a natural demethylation agent targeting WIF1 to prevent breast cancer. ISL administration suppressed in vivo breast cancer initiation and progression, accompanied by reduced CSC-like populations. A global gene expression profile assay further identified WIF1 as the main response gene of ISL treatment, accompanied by the simultaneous downregulation of β-catenin signaling and G0/G1 phase arrest in breast CSCs. In addition, WIF1 inhibition significantly relieved the CSC-limiting effects of ISL and methylation analysis further revealed that ISL enhanced WIF1 gene expression via promoting the demethylation of its promoter, which was closely correlated with the inhibition of DNMT1 methyltransferase. Molecular docking analysis finally revealed that ISL could stably dock into the catalytic domain of DNMT1. Taken together, our findings not only provide preclinical evidence to demonstrate the use of ISL as a dietary supplement to inhibit mammary carcinogenesis but also shed novel light on WIF1 as an epigenetic target for breast cancer prevention.

No MeSH data available.


Related in: MedlinePlus