Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

Lin, Chi‐Hui; Pelissier, Fanny A.; Zhang, Hui; lakins, Jon; Weaver, Valerie M.; Park, Catherine; LaBarge, Mark A.

doi:10.1091/mbc.e15-07-0456

Cited by 130 publications

(111 citation statements)

References 49 publications

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“…16 Next, evidence that both estrogens, via G proteincoupled estrogen receptor (GPER), and HER2 via mechanotransduction, intersect the Hippo pathway corroborates the hypothesis of molecular subtype-dependent levels of Hippo pathway regulation in BC. 27,28 The data herein presented provide hints which may help shape a molecular scenario where Hippo kinases exert distinct functions in relation to the underlying molecular background (subtype) of BC. However, the limitations potentially arising from the use of one single investigational approach, i.e., immunostaining, along with the hypothesis generating nature of the evidence provided, prompted the design of ad hoc studies in adequately sized cohorts to investigate the topic of interest to a deeper extent, with special emphasis being placed on TNBC given the well-established defects in the DDR machinery carried by this disease.…”

Section: Discussionmentioning

confidence: 88%

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Ercolani¹,

Benedetto²,

Terrenato

et al. 2017

Cancer Biology & Therapy

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The Hippo kinases MST1/2 and LATS1/2 inhibit the oncoproteins TAZ/YAP and regulate T cell function. Hippo kinases also cooperate with the ATR-Chk1 and ATM-Chk2 pathways, central orchestrators of the DNA damage response (DDR). We hypothesized that MST1/2 and LATS1/2 localization differently impacts the efficacy of neoadjuvant therapy (NAT) in breast cancer, being protective when expressed in the cytoplasm of tumor cells and in tumor-infiltrating lymphocytes, whereas representing molecular determinants of chemoresistance when present in the nucleus as a consequence of their cooperation with the DDR. Diagnostic biopsies from 57 HER2-positive and triple-negative breast cancer patients treated with NAT were immunostained for evaluating the expression of phosphorylated MST1/2 (pMST1/2) and LATS1/2 (pLATS1/2) in tumor-infiltrating lymphocytes (TILs) and in cancer cells. TAZ and Chk1 immunostaining was exploited for investigating subcellular compartment-dependent activity of Hippo kinases. Nuclear pMST1/2 (pMST1/2 nuc ) expression was significantly associated with nuclear expression of Chk1 (p D 0.046), whereas cytoplasmic pMST1/2 (pMST1/2 cyt ) expression was marginally associated with cytoplasmic TAZ staining (p D 0.053). Patients whose tumors expressed pMST1/2 nuc were at increased risk of residual disease after NAT (pCR ypT0/is ypN0: OR 4.91, 95%CI: 1.57-15.30; pCR ypT0 ypN0: OR 3.59, 95%CI 1.14-11.34). Conversely, exclusive cytoplasmic localization of pMST1/2 (pMST1/2 cyt )seemed to be a protective factor (pCR ypT0/is ypN0: OR 0.34, 95%CI: 0.11-1.00; pCR ypT0 ypN0: OR 0.31, 95%CI 0.10-0.93). The subcellular localization-dependent significance of pMST1/2 expression suggests their involvement in different molecular networks with opposite impact on NAT efficacy. Larger studies are warranted to confirm these novel findings.KEYWORDS HER2-positive breast cancer; Hippo pathway; LATS 1/2; MST1/2; triple-negative breast cancer

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Section: Discussionmentioning

confidence: 88%

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Ercolani¹,

Benedetto²,

Terrenato

et al. 2017

Cancer Biology & Therapy

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“…Finally, a high expression of YAP is closely associated with TKI resistance in lung cancer [22]. Given the important role of YAP in lung cancer cells, we subsequently examined the expression of YAP in LLC and PC-9 cells lines that originated from human lung cancer specimens.…”

Section: Discussionmentioning

confidence: 99%

Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy

Zhang¹,

Pan²,

Liao³

et al. 2018

Trop. J. Pharm Res

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“…Lately, VP has shown promising anticancer effect in various malignancies such as breast cancer,13,14 prostate carcinoma,15 pancreatic ductal adenocarcinoma,16 and esophageal cancer,17 especially when combined with standard chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

Feng¹,

Gou²,

Jia³

et al. 2016

OTT

114

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Yes-associated protein (YAP) is a key transcriptional coactivator of Hippo pathway and has been shown to be an oncoprotein in ovarian cancer (OC). Verteporfin (VP), clinically used in photodynamic therapy for neovascular macular degeneration, has been recently proven to be a suppressor of YAP–TEAD complex and has shown potential in anticancer treatment. In this study, we aimed to explore the potential effect of VP in the treatment of OC. Our results showed that VP led to inhibition of proliferation in a time- and dose-dependent manner and to the suppression of migratory and invasive capacities of OC cells. Western blot and real-time polymerase chain reaction demonstrated that VP induced YAP cytoplasmic retention and deregulated inducible YAP and CCNs in OC cells. In vivo, VP exerted a significant effect on tumor growth in OVCAR8 xenograft mice, resulting in tumor nodules with lower average weight and reduced volume of gross ascites. In addition, VP treatment remarkably upregulated cytoplasmic YAP and phosphorylation YAP and downregulated CCN1 and CCN2, but exerted little effect on YAP-upstream components in Hippo pathway. In conclusion, our results suggested that VP may be a promising agent for OC, acting by suppressing YAP–TEAD complex.

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Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

Cited by 130 publications

References 49 publications

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy

Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer

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Microenvironment rigidity modulates responses to the HER2 receptor tyrosine kinase inhibitor lapatinib via YAP and TAZ transcription factors

Cited by 130 publications

References 49 publications

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Expression of phosphorylated Hippo pathway kinases (MST1/2 and LATS1/2) in HER2-positive and triple-negative breast cancer patients treated with neoadjuvant therapy

Peptide 17, an inhibitor of YAP/TEAD4 pathway, mitigates lung cancer malignancy

Verteporfin, a suppressor of YAP&ndash;TEAD complex, presents promising antitumor properties on ovarian cancer

Contact Info

Product

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Verteporfin, a suppressor of YAP–TEAD complex, presents promising antitumor properties on ovarian cancer