Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Li, Shan; Feng, Tingting; Guo, Yang; Lei, Yu; Huang, Qingqing; Zhang, Liang; Tang, Wei; Liu, Ying

doi:10.3892/ol.2016.5374

Cited by 8 publications

(8 citation statements)

References 28 publications

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“…Moreover, CIP2A depletion in TNBC cell lines resulted in inhibition of proliferation and invasion, on one hand, and induction of apoptosis and autophagy on the other hand. Another study showed that increased CIP2A expression was significantly related to basal-like and HER2+ breast cancers [40].…”

Section: Discussionmentioning

confidence: 99%

Assessment of CIP2A and ROCK-I expression and their prognostic value in breast cancer

Osman¹,

Khalaf²,

Ibraheem³

2020

pjp

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Breast cancer is the most leading cause of cancer death in females worldwide. Identification of novel biomarkers for prognosis is required. Imunohistochemical evaluation of CIP2A and ROCK-1 expressions in 126 breast tissue specimens stratified as 21 ductal hyperplasias, 17 duct carcinoma in situ (DCIS) and 88 invasive carcinomas (56 invasive ductal carcinomas NST, 32 invasive lobular carcinomas) was studied. High CIP2A expression was detected in 48.9% of invasive carcinomas. CIP2A overexpression was significantly related to Nottingham prognostic index (NPI) (p = 0.011), stage (p = 0.01), ER negativity (p = 0.031), PR negativity (p = 0.048), and HER-2 positivity (p = 0.02). CIP2A was significantly overexpressed in triple-negative breast cancer (TNBC) (p = 0.004). ROCK-1 expression was detected in 54.5% of invasive carcinomas. Statistically significant associations were observed between ROCK-1 expression and NPI (p = 0.032), stage (p = 0.002), ER negativity (p = 0.012), PR negativity (p = 0.023), HER-2 positivity (p = 0.016), and TNBC subtype (p = 0.033). A positive association between CIP2A and ROCK-1 expressions (p < 0.0001) was documented. There was a significant association between shorter overall survival and high CIP2A and positive ROCK-1 expressions (p < 0.0001) and (p < 0.0001). CIP2A and ROCK-1 expressions could be used as markers for the poor prognosis of breast cancer.

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Section: Discussionmentioning

confidence: 99%

Assessment of CIP2A and ROCK-I expression and their prognostic value in breast cancer

Osman¹,

Khalaf²,

Ibraheem³

2020

pjp

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“…Previous studies, including ours reported that CIP2A promoted the aggressiveness of breast cancer (23,24). Next, we examined the effect of CIP2A depletion on Atn-inhibited invasive behavior.…”

Section: Resultsmentioning

confidence: 99%

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

et al. 2017

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Abstract.We have shown that a novel STAT3 inhibitor arctigenin (Atn) induces significant cytotoxicity in triple-negative breast cancer (TNBC) cells. This study further delineated molecular mechanisms where by Atn triggered cytotoxicity in TNBC cells. We found Atn can also inhibit metastasis in TNBC cells through cancerous inhibitor of protein phosphatase 2A (CIP2A) pathway. CIP2A is an endogenous inhibitor of protein phosphatase 2A (PP2A), which can increase the migration and invasion of various cancer cells. PP2A is a tumor suppressor, which is functionally defective in various cancers. Atn-induced metastasis inhibition was associated with reactivation of PP2A, downregulation of CIP2A and Akt phosphorylation. Silencing CIP2A enhanced Atn-induced metastasis inhibition and apoptosis in TNBCs. Furthermore, ectopic expression of CIP2A or inhibition of PP2A in TNBC cells abolished the effects of Atn. In conclusion, we found that enhancement of PP2A activity by inhibition of CIP2A, at least in part, promotes the anti-metastasis effect induced by Atn. Our findings disclose the novel therapeutic mechanism of this targeted agent, and suggest the therapeutic potential and feasibility of developing PP2A enhancers as a novel anticancer strategy.

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“…Among the three inhibitors, only Akt specific inhibitor LY294002 was able to downregulate CIP2A, similar to lapatinib treatment. Although mTOR activation is correlated with CIP2A deregulation [ 40 , 41 ], mTOR inhibition via rapamycin treatment did not suppress CIP2A expression, indicating that CIP2A-induced mTOR activation observed in our study is likely a result of CIP2A-Akt interactions (Figure 4 ). Together, our results suggest that lapatinib-induced inactivation of the PI3K/Akt pathway stimulates consequential CIP2A downregulation, and Akt activity is a critical regulator of CIP2A.…”

Section: Discussionmentioning

confidence: 54%

Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells

et al. 2017

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Lapatinib, a small molecule ErbB2/EGFR inhibitor, is FDA-approved for the treatment of metastatic ErbB2-overexpressing breast cancer; however, lapatinib resistance is an emerging clinical challenge. Understanding the molecular mechanisms of lapatinib-mediated anti-cancer activities and identifying relevant resistance factors are of pivotal significance. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is a recently identified oncoprotein that is overexpressed in breast cancer. Our study investigated the role of CIP2A in the anti-cancer efficacy of lapatinib in ErbB2-overexpressing breast cancer cells. We found that lapatinib concurrently downregulated CIP2A and receptor tyrosine kinase signaling in ErbB2-overexpressing SKBR3 and 78617 cells; however, these effects were attenuated in lapatinib-resistant (LR) cells. CIP2A overexpression rendered SKBR3 and 78617 cells resistant to lapatinib-induced apoptosis and growth inhibition. Conversely, CIP2A knockdown via lentiviral shRNA enhanced cell sensitivity to lapatinib-induced growth inhibition and apoptosis. Results also suggested that lapatinib downregulated CIP2A through regulation of protein stability. We further demonstrated that lapatinib-induced CIP2A downregulation can be recapitulated by LY294002, suggesting that Akt mediates CIP2A upregulation. Importantly, lapatinib induced differential CIP2A downregulation between parental BT474 and BT474/LR cell lines. Moreover, CIP2A shRNA knockdown significantly sensitized the BT474/LR cells to lapatinib. Collectively, our results demonstrate that CIP2A is a molecular target and resistance factor of lapatinib with a critical role in lapatinib-induced cellular responses, including the inhibition of the CIP2A-Akt feedback loop. Further investigation of lapatinib-mediated CIP2A regulation will advance our understanding of lapatinib-associated anti-tumor activities and drug resistance.

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Expression of cancerous inhibitor of protein phosphatase 2A in human triple negative breast cancer correlates with tumor survival, invasion and autophagy

Cited by 8 publications

References 28 publications

Assessment of CIP2A and ROCK-I expression and their prognostic value in breast cancer

Assessment of CIP2A and ROCK-I expression and their prognostic value in breast cancer

Arctigenin inhibits triple-negative breast cancers by targeting CIP2A to reactivate protein phosphatase 2A

Activation of cancerous inhibitor of PP2A (CIP2A) contributes to lapatinib resistance through induction of CIP2A-Akt feedback loop in ErbB2-positive breast cancer cells

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