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Inhibition of Yes-Associated Protein-1 (YAP1) Enhances the Response of Invasive Breast Cancer Cells to the Standard
Maha Guimei1,2, Sana Alrouh3, Maha Saber-Ayad2,3,4
1Department of Pathology, Faculty of Medicine, Alexandria University, Alexandria, Egypt.
Purpose:
The deregulation of the Hippo pathway results in translocation ofYes-associated protein-1 (YAP1) to the nucleus to exert an oncogenic effect. This effect has been demonstrated in several malignancies, yet, in breast cancer (BC), it remains controversial. The present study aimed to investigate the significance of YAP1 expression in BC, its relation to cancer stem cells (CSCs), and the effect of its inhibition on tumor cell survival.
Patients And Methods:
We evaluated the expression of YAP1 protein and gene using immunohistochemistry (IHC) and RT-qPCR in FFPE tissue from normal and breast cancer cases. We also studied its association with CSC expression (OCT4, NANOG, and SOX2) and with different clinicopathologic characteristics. Two BC cell lines (MCF7 and MDA-MB-231) were exposed to different concentrations of YAP1 inhibitor "verteporfin" and cell viability was subsequently assessed.
Results:
YAP1 mRNA was higher in BC compared to the normal breast tissue (p-value=0.040) and was higher in luminal tumors compared to triple-negative breast cancer (TNBC) (p-value= 0.017). Its expression in tumors was significantly associated with the expression of pluripotency markers (OCT4 and NANOG) (p-value= 0.030 and 0.035, respectively) and its inhibition resulted in a significant reduction of CSC expression in both MCF-7 and MDA-MB-231 cells. YAP1 nuclear expression by IHC, which signifies its activation, was more evident in invasive carcinomas compared to normal breast tissue and in-situ foci where the expression was limited to the cytoplasm. The pretreatment of BC cells (MCF7 and MDA-MB-231) with YAP1 inhibitor "verteporfin" resulted in their sensitization to the effect of tamoxifen and doxorubicin, respectively, and significantly decreased tumor cell proliferation and survival.
Conclusion:
Our results imply that YAP1 is highly expressed and activated in BC and its inhibition could represent a possible novel therapeutic strategy that should be further explored and investigated to improve the outcome of breast cancer patients.
Insights
Yes-associated protein-1 (YAP1) is highly expressed in breast cancer (BC) and linked to cancer stem cells. Inhibiting YAP1 reduced tumor cell survival and CSC markers, suggesting it as a potential therapeutic target for BC.
Area of Science:
- Oncology
- Molecular Biology
- Cell Biology
Background:
- Deregulation of the Hippo pathway leads to Yes-associated protein-1 (YAP1) nuclear translocation and oncogenic effects.
- YAP1's role in breast cancer (BC) remains controversial, necessitating further investigation.
- Cancer stem cells (CSCs) are implicated in tumor development and resistance to therapy.
Purpose of the Study:
- To investigate the significance of YAP1 expression in breast cancer.
- To explore the relationship between YAP1 and cancer stem cell markers (OCT4, NANOG, SOX2).
- To evaluate the effect of YAP1 inhibition on breast cancer cell survival and CSC markers.
Main Methods:
- YAP1, OCT4, NANOG, and SOX2 expression were assessed using immunohistochemistry and RT-qPCR in breast cancer tissues.
- Breast cancer cell lines (MCF7, MDA-MB-231) were treated with the YAP1 inhibitor verteporfin.
- Cell viability and CSC marker expression were evaluated post-treatment.
Main Results:
- YAP1 mRNA levels were significantly higher in breast cancer compared to normal tissue and in luminal tumors versus triple-negative breast cancer (TNBC).
- YAP1 expression correlated significantly with OCT4 and NANOG expression, key pluripotency markers.
- YAP1 inhibition by verteporfin reduced CSC marker expression, decreased tumor cell proliferation and survival, and sensitized cells to chemotherapy.
Conclusions:
- YAP1 is highly expressed and activated in breast cancer, associating with CSC markers.
- YAP1 inhibition demonstrates a promising therapeutic strategy for breast cancer.
- Further research into YAP1 inhibition is warranted to improve breast cancer patient outcomes.
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