Abstract
BackgroundYAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. Despite various studies, the role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. Therefore in the present study we aimed to investigate YAP at DNA, mRNA and protein level and also attempted to correlate our molecular findings with various clinicopathological variables of the patients.MethodsThe study comprised of a total 137 genetically unrelated women with sporadic breast cancer cases and normal adjacent tissues not infiltrated with tumor. Mutation of YAP gene was analyzed by automated DNA sequencing. YAP promoter methylation was studied using MS-PCR. Expression at mRNA and protein level was studied using qPCR and IHC respectively.ResultsIn our study YAP mRNA expression was found to be 8.65 ± 6.17 fold downregulated in 67.15% cases. The expression of YAP when analyzed at the protein level by IHC was found to be absent in 78.83% cases. Results from MS-PCR analysis showed that YAP promoter methylation plays an important role in declining the expression of YAP protein. The absence of YAP protein coincided with 86.60% methylated cases thereby showing a very strong correlation (p = 0.001). We also investigated YAP mutation at the major check point sites in the Hippo pathway and observed no mutation. A significant association was observed on correlating mRNA expression with clinical stages (p = 0.038) and protein expression with ER status (p = 0.018) among Indian breast cancer patients.ConclusionThe expression of YAP was found to be downregulated in response to aberrant promoter methylation. The downregulation of YAP are consistent with previous studies suggesting it to have a tumor suppressive role in breast cancer. We did not observe any mutation at the major check point sites in the Hippo pathway.
Highlights
Yes-associated protein (YAP), a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved
Downregulated YAP mRNA expression in breast cancer tissue YAP mRNA expression was detected at the mRNA level in normal and breast cancer tissues
YAP mRNA expression was found to be downregulated in 67.15% cases (92/137), out of which 60.87% cases (56/92) belonged to advanced stages III and IV of breast cancer
Summary
YAP, a potent oncogene and major downstream effector of the mammalian Hippo tumor suppressor pathway can act as either oncogene or tumor suppressor gene based on the type of tissue involved. The role and mechanism through which YAP mediates its tumor suppressor or oncogenic effects are not yet fully understood. In the present study we aimed to investigate YAP at DNA, mRNA and protein level and attempted to correlate our molecular findings with various clinicopathological variables of the patients. Breast cancer involves the interconnection of various signaling pathways [2]. An emerging tumor suppressor pathway plays a pivotal. YAP (Yes-associated protein) is a potent oncogene present at 11q22 amplicon and major downstream effector of the mammalian Hippo tumor suppressor pathway [5, 6]. Cell-to-cell contacts lead to the activation of Hippo pathway which in turn leads to the phosphorylation of YAP at various serine residues including serine 127 by concerted action of LATS and MST, two uptream kinases and is secluded from the nucleus by 14-3-3 proteins decreasing the transcriptional activities
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