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DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer.

Yin X, Xiang T, Li L, Su X, Shu X, Luo X, Huang J, Yuan Y, Peng W, Oberst M, Kelly K, Ren G, Tao Q - Breast Cancer Res. (2013)

Bottom Line: We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues.Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.

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ABSTRACT

Introduction: Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in breast tumorigenesis remains unclear.

Methods: We examined DACT1 expression in breast cancer cell lines and primary tumors with semiquantitative or quantitative RT-PCR and immunochemistry, and further evaluated the promoter methylation of DACT1 with methylation-specific PCR (MSP). We also explored the tumor-suppressive functions of DACT1 in vivo and in vitro, and its related mechanism in breast cancer.

Results: We identified DACT1 as a methylated target in our breast cancer epigenome study. Here, we further investigated DACT1 expression in multiple breast cell lines and primary tumors, and further studied its function and molecular mechanisms. We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues. Promoter CpG methylation of DACT1 was detected in five (55.6%) of nine breast cancer cell lines and 40 (29.9%) of 134 primary tumors, but not in surgical-margin tissues and normal breast tissues. Demethylation treatment of breast cancer cell lines restored DACT1 expression along with promoter demethylation, suggesting that an epigenetic mechanism mediates DACT1 silencing in breast cancer. Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.

Conclusions: Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.

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Wound-healing assay for cell motility of vector- or DACT1-transfected MB231 and MCF7 cells. Upper: Representative images of wound sealing at 0 hours and 42 or 48 hours after wound scratch. Lower: The percentage of wound sealing compared with that of controls at each time point as indicated.
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Figure 6: Wound-healing assay for cell motility of vector- or DACT1-transfected MB231 and MCF7 cells. Upper: Representative images of wound sealing at 0 hours and 42 or 48 hours after wound scratch. Lower: The percentage of wound sealing compared with that of controls at each time point as indicated.

Mentions: As the Wnt/β-catenin signaling pathway plays a key role in tumor metastasis, the effect of DACT1 on cell migration was further analyzed. Wound-healing assay showed that MB231 and MCF7 cells migrated into scraped areas within 42 and 48 hours, whereas DACT1 expression decreased their wound closure by about 55% after 42 hours and about 70% after 48 hours in these two cell lines (Figure 6), suggesting that DACT1 attenuates the wound-induced cell migration of breast cancer.


DACT1, an antagonist to Wnt/β-catenin signaling, suppresses tumor cell growth and is frequently silenced in breast cancer.

Yin X, Xiang T, Li L, Su X, Shu X, Luo X, Huang J, Yuan Y, Peng W, Oberst M, Kelly K, Ren G, Tao Q - Breast Cancer Res. (2013)

Wound-healing assay for cell motility of vector- or DACT1-transfected MB231 and MCF7 cells. Upper: Representative images of wound sealing at 0 hours and 42 or 48 hours after wound scratch. Lower: The percentage of wound sealing compared with that of controls at each time point as indicated.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3672711&req=5

Figure 6: Wound-healing assay for cell motility of vector- or DACT1-transfected MB231 and MCF7 cells. Upper: Representative images of wound sealing at 0 hours and 42 or 48 hours after wound scratch. Lower: The percentage of wound sealing compared with that of controls at each time point as indicated.
Mentions: As the Wnt/β-catenin signaling pathway plays a key role in tumor metastasis, the effect of DACT1 on cell migration was further analyzed. Wound-healing assay showed that MB231 and MCF7 cells migrated into scraped areas within 42 and 48 hours, whereas DACT1 expression decreased their wound closure by about 55% after 42 hours and about 70% after 48 hours in these two cell lines (Figure 6), suggesting that DACT1 attenuates the wound-induced cell migration of breast cancer.

Bottom Line: We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues.Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.

View Article: PubMed Central - HTML - PubMed

ABSTRACT

Introduction: Aberrant activation of Wnt/β-catenin signaling plays an important role in the pathogenesis of breast cancer. DACT1 (Dapper/Frodo) has been identified as involved in antagonizing Wnt/β-catenin signaling through interacting with Dishevelled (Dvl), a central mediator of Wnt signaling, whereas its role in breast tumorigenesis remains unclear.

Methods: We examined DACT1 expression in breast cancer cell lines and primary tumors with semiquantitative or quantitative RT-PCR and immunochemistry, and further evaluated the promoter methylation of DACT1 with methylation-specific PCR (MSP). We also explored the tumor-suppressive functions of DACT1 in vivo and in vitro, and its related mechanism in breast cancer.

Results: We identified DACT1 as a methylated target in our breast cancer epigenome study. Here, we further investigated DACT1 expression in multiple breast cell lines and primary tumors, and further studied its function and molecular mechanisms. We found that DACT1 expression was silenced in eight (88.9%) of nine breast cancer cell lines, and its protein levels were obviously reduced in breast tumors compared with paired surgical-margin tissues. Promoter CpG methylation of DACT1 was detected in five (55.6%) of nine breast cancer cell lines and 40 (29.9%) of 134 primary tumors, but not in surgical-margin tissues and normal breast tissues. Demethylation treatment of breast cancer cell lines restored DACT1 expression along with promoter demethylation, suggesting that an epigenetic mechanism mediates DACT1 silencing in breast cancer. Functional assays showed that ectopic expression of DACT1 could inhibit breast tumor cell proliferation in vivo and in vitro through inducing apoptosis, and further suppress tumor cell migration through antagonizing the Wnt/β-catenin signaling pathway.

Conclusions: Our study demonstrates that DACT1 could function as a tumor suppressor but was frequently downregulated in breast cancer.

Show MeSH
Related in: MedlinePlus