Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Díaz‐Martín, Juan; López-García, María Ángeles; Romero‐Pérez, Laura; Atienza-Amores, María Reina; Pecero, María Luisa; Castilla, María Ángeles; Biscuola, Michele; Santón, Almudena; Palacios, José

doi:10.1530/erc-14-0456

Cited by 74 publications

(62 citation statements)

References 36 publications

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“…For example, activation of YAP is highly associated with poor prognosis and treatment resistance in colorectal cancer41 and promotes migration and invasion in prostate cancers cells42. In addition, nuclear TAZ is present in 90% of metaplastic (a subtype of triple negative) breast cancers with EMT morphology43. YAP and TAZ have also been associated with progression and metastasis in lung cancer44 and their direct transcription targets, CTGF and AXL, were linked to EMT and drug resistance in this disease45.…”

Section: Discussionmentioning

confidence: 99%

Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

Vahid

Thaper

Gibson

et al. 2016

Sci Rep

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Heat shock protein 27 (Hsp27) is a molecular chaperone highly expressed in aggressive cancers, where it is involved in numerous pro-tumorigenic signaling pathways. Using functional genomics we identified for the first time that Hsp27 regulates the gene signature of transcriptional co-activators YAP and TAZ, which are negatively regulated by the Hippo Tumor Suppressor pathway. The Hippo pathway inactivates YAP by phosphorylating and increasing its cytoplasmic retention with the 14.3.3 proteins. Gain and loss of function experiments in prostate, breast and lung cancer cells showed that Hsp27 knockdown induced YAP phosphorylation and cytoplasmic localization while overexpression of Hsp27 displayed opposite results. Mechanistically, Hsp27 regulates the Hippo pathway by accelerating the proteasomal degradation of ubiquitinated MST1, the core Hippo kinase, resulting in reduced phosphorylation/activity of LATS1 and MOB1, its downstream effectors. Importantly, our in vitro results were supported by data from human tumors; clinically, high expression of Hsp27 in prostate tumors is correlated with increased expression of YAP gene signature and reduced phosphorylation of YAP in lung and invasive breast cancer clinical samples. This study reveals for the first time a link between Hsp27 and the Hippo cascade, providing a novel mechanism of deregulation of this tumor suppressor pathway across multiple cancers.

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Section: Discussionmentioning

confidence: 99%

Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

Vahid

Thaper

Gibson

et al. 2016

Sci Rep

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“…A subset of samples was immunostained for TAZ and Chk1, 10,16 enabling us to investigate whether subcellular localization of Hippo kinases is consistent with their participation in different molecular circuits, namely the Hippo signaling cascade for cytoplasmic localization and the DDR for nuclear localization. The choice of the aforementioned BC molecular subtypes is rooted into i) the emerging relationship between deregulation of the Hippo machinery and the most aggressive BC subtypes, 3,6,17 ii) a wider use of NAT in HER2-positive and TNBC patients compared with patients diagnosed with HER2-negative/hormone receptor positive diseases, and iii) our previous studies providing initial hints on the predictive significance of Hippo biomarkers in the HER2-positive and TNBC backgrounds.…”

Section: Introductionmentioning

confidence: 99%

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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“…Our group has recently promoted translational studies aimed at characterizing this emerging BCSC pathway in cancer patients, with the goal of identifying potential prognostic and predictive biomarkers. Results from exploratory analyses in FBC patients provided the first clues that the expression of Hippo transducers may confer poorer clinical outcomes [35, 36]. …”

Section: Introductionmentioning

confidence: 99%

The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer

Benedetto¹,

Mottolese²,

Sperati³

et al. 2016

Oncotarget

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Male breast cancer (MBC) is a rare disease and its biology is poorly understood. Deregulated Hippo pathway promotes oncogenic functions in female breast cancer. We herein investigated the expression of the Hippo transducers TAZ/YAP and their target CTGF in MBC. Tissue microarrays containing samples from 255 MBC patients were immunostained for TAZ, YAP and CTGF. One hundred and twenty-nine patients were considered eligible. The Pearson's Chi-squared test of independence was used to test the association between categorical variables. The correlation between TAZ, YAP and CTGF was assessed with the Pearson's correlation coefficient. The Kaplan-Meier method and the log-rank test were used for estimating and comparing survival curves. Cox proportional regression models were built to identify variables impacting overall survival. Statistical tests were two-sided. Tumors were considered to harbor active TAZ/YAP-driven gene transcription when they co-expressed TAZ, or YAP, and CTGF. Patients whose tumors had the TAZ/CTGF and YAP/CTGF phenotypes experienced shorter overall survival compared with their negative counterparts (log rank p = 0.036 for both). TAZ/CTGF and YAP/CTGF tumors were associated with decreased survival in patients with invasive ductal carcinomas, G3 tumors, hormone receptor-positive tumors, and tumors with elevated Ki-67. Multivariate analyses confirmed that the TAZ/CTGF and YAP/CTGF phenotypes are independent predictors of survival (HR 2.03, 95% CI: 1.06–3.90, p = 0.033; and HR 2.00, 95% CI: 1.04–3.84, p = 0.037 respectively). Comparable results were obtained when excluding uncommon histotypes (TAZ/CTGF: HR 2.34, 95% CI: 1.16–4.73, p = 0.018. YAP/CTGF: HR 2.36, 95% CI: 1.17–4.77, p = 0.017). Overall, the TAZ/YAP-driven oncogenic program may be active in MBC, conferring poorer survival.

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Nuclear TAZ expression associates with the triple-negative phenotype in breast cancer

Cited by 74 publications

References 36 publications

Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

Molecular chaperone Hsp27 regulates the Hippo tumor suppressor pathway in cancer

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

The Hippo transducers TAZ/YAP and their target CTGF in male breast cancer

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