Prognostic significance of RACGAP1 mRNA expression in high-risk early breast cancer: a study in primary tumors of breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial

Pliarchopoulou, Kyriaki; Kalogeras, Konstantine T.; Kronenwett, Ralf; Wirtz, Ralph M.; Eleftheraki, Anastasia G; Batistatou, Anna; Bobos, Mattheos; Soupos, Nikolaos; Polychronidou, Genovefa; Gogas, Helen; Samantas, E.; Christodoulou, Christos; Makatsoris, Thomas; Pavlidis, Nicholas; Pectasides, Dimitrios; Fountzilas, George

doi:10.1007/s00280-012-2002-z

Cited by 48 publications

(43 citation statements)

References 35 publications

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“…HR hazard ratio, CI confidence interval RacGAP1 in gastric cancer 89 histological grade tumors were associated with high RACGAP1 gene expression [7,14]. Although our transcriptional analysis was similar to previous reports, it is difficult to explain the reason for the different results obtained by immunohistochemical and transcriptional evaluations.…”

Section: Discussionsupporting

confidence: 28%

“…Moreover, RacGAP1 is involved in cell transformation, motility, migration, and metastasis [9][10][11][12]. The clinical significance of RacGAP1 has been reported in several malignancies such as meningioma, breast cancer, and hepatocellular carcinoma [7,8,[13][14][15]. The previous studies suggested that high RacGAP1 expression reflected increased aggressiveness of the tumor.…”

Section: Introductionmentioning

confidence: 99%

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Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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Background Rac GTPase activating protein 1 (RacGAP1) plays a regulatory role in cell growth, transformation and metastasis. The aim of this study was to clarify the association between RacGAP1 expression and clinical outcome in patients with gastric cancer. Methods A total of 232 gastric cancer patients in our institute who underwent surgery without preoperative treatments were enrolled in this study. We investigated RacGAP1 expression using immunohistochemistry (IHC) and evaluated IHC scores calculated by the percentage of positive cells and intensity and its expression at the invasive front. RACGAP1 expression was also assessed. Results RacGAP1 expression was observed in the nuclei of gastric cancer cells. Evaluation by IHC score showed no significant correlations with clinicopathological variables except for histological differentiation. In transcriptional analyses, RACGAP1 expression was elevated in diffuse type gastric cancer than intestinal type without a significant difference. We observed significant correlations of Rac-GAP1 protein expression at the invasive front with older age, tumor size, lymph node metastasis, lymphatic invasion, vascular invasion and advanced stage. Patients with RacGAP1 protein expression at the invasive front had significantly poorer prognosis than those without it (P \ 0.0001). In multivariate analysis, lymph node metastasis, distant metastasis and positive RacGAP1 expression at the invasive front were independent prognostic factors (lymph node metastasis: P = 0.0106; distant metastasis: P = 0.0012; RacGAP1: P = 0.0011). Conclusions RacGAP1 expression at the invasive front in gastric cancer was significantly correlated with factors reflecting tumor progression and poor prognosis. Our data suggest that RacGAP1 might play important roles in the progression of gastric cancer.

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Section: Discussionsupporting

confidence: 28%

Section: Introductionmentioning

confidence: 99%

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

et al. 2014

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“…This is also the first report to show that overexpression of tumor-associated RacGAP1 is directly controlled by E2F7, which itself is known to be overexpressed in SCC and to induce drug resistance (15). Overexpression of RacGAP1 has been reported in high-grade meningiomas, non-small cell lung cancer, gastric cancer, hepatocellular carcinoma, breast cancer (24,38,(42)(43)(44) as well as in the more aggressive tumor phenotypes of epithelial ovarian cancer, highgrade breast cancer, and invasive cervical cancer (45)(46)(47). However, it is unknown whether the overexpression of RacGAP1 in these tumors is linked to overexpression of E2F7.…”

Section: Discussionmentioning

confidence: 94%

“…The Rho family of GTPases is a subfamily of the Ras superfamily and consists of small signaling G proteins: Rho (A, B, and C isoforms), Rac (1,2,3 isoforms and RhoG), and Cdc42 (Cdc42, Tc10, TCL, Chp/Wrch-2, and Wrch-1; ref. 24), which function as molecular switches between a GTP-loaded "ON" and a GDP-loaded "OFF" state (24). Thus, RacGAP1 has the potential to regulate a diverse array of cellular functions through its central role as a regulator of the activation state of the Rho family of GTPases.…”

Section: Racgap1 Is a Novel Downstream Effector Of E2f7mentioning

confidence: 99%

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

Hazar-Rethinam

Long

Gannon

et al. 2015

Molecular Cancer Therapeutics

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We have previously shown that E2F7 contributes to drug resistance in head and neck squamous cell carcinoma (HNSCC) cells. Considering that dysregulation of responses to chemotherapy-induced cytotoxicity is one of the major reasons for treatment failure in HNSCC, identifying the downstream effectors that regulate E2F7-dependent sensitivity to chemotherapeutic agents may have direct clinical impact. We used transcriptomic profiling to identify candidate pathways that contribute to E2F7-dependent resistance to doxorubicin. We then manipulated the expression of the candidate pathway using overexpression and knockdown in in vitro and in vivo models of SCC to demonstrate causality. In addition, we examined the expression of E2F7 and RacGAP1 in a custom tissue microarray (TMA) generated from HNSCC patient samples. Transcriptomic profiling identified RacGAP1 as a potential mediator of E2F7-dependent drug resistance. We validated E2F7-dependent upregulation of RacGAP1 in doxorubicininsensitive SCC25 cells. Extending this, we found that selective upregulation of RacGAP1 induced doxorubicin resistance in previously sensitive KJDSV40. Similarly, stable knockdown of RacGAP1 in insensitive SCC25 cells induced sensitivity to doxorubicin in vitro and in vivo. RacGAP1 expression was validated in a TMA, and we showed that HNSCCs that overexpress RacGAP1 are associated with a poorer patient overall survival. Furthermore, E2F7-induced doxorubicin resistance was mediated via RacGAP1-dependent activation of AKT. Finally, we show that SCC cells deficient in RacGAP1 grow slower and are sensitized to the cytotoxic actions of doxorubicin in vivo. These findings identify RacGAP1 overexpression as a novel prognostic marker of survival and a potential target to sensitize SCC to doxorubicin.

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“…RacGAP1 is also essential for cell division (Zhao and Fang, 2005) and embryogenesis (O'Brien et al, 2010). The role of RacGAP1 in breast cancer has been recently explored in a large series of patient samples with high-risk early breast cancer (Pliarchopoulou et al, 2013). The expression of RacGAP1 mRNA from 314 samples found an association between high RacGAP1 expression and high-grade and strongly Ki67 expressing tumours, and patients had poor overall survival and poor disease free survival compared with patients with low RacGAP1 expression.…”

Section: Racgap1 May Be Important In Her2 Expressing Breast Tumoursmentioning

confidence: 99%

Intratumour heterogeneity in the development and progression of breast cancer

Kutasovic¹

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The extent of intratumour heterogeneity and its clinical implications are poorly understood.This thesis addresses this theme of tumour heterogeneity with a broad focus on invasive lobular carcinomas of the breast. More specifically the focus will be on studying the various mechanisms of deregulation of E-cadherin, the morphological and phenotypic variation mixed ductal lobular carcinomas, and finally heterogeneity of metastatic progression.Invasive lobular carcinoma (ILC) is the second most common breast cancer subtype, accounting for 10-15% of the all breast cancers, and is the most common 'special type'.Biologically, the most distinguishing feature of ILC is the loss of the cellular adhesion molecule E-cadherin (absent in up to 90% of ILC), and this is considered fundamental to development of the characteristic infiltrative growth pattern. The deregulation of Ecadherin is not fully understood, and so this thesis aims to investigate the mechanisms of E-cadherin deregulation in tumourigenesis. Co-localised with E-cadherin at the cell membrane are a series of proteins (including ECT2, RacGAP1 and N-WASP) which regulate the actin cytoskeleton; the expression of these proteins was investigated using immunohistochemistry (IHC) of breast cancer tissue microarrays (Chapter 3). Differences in cytoplasmic expression and localisation of these molecules were found between different histological types and clinicopathological parameters that warrant further investigation. It remains unclear whether these molecules contribute to deregulating cell adhesion in vivo.Mixed ductal-lobular carcinomas (MDL) display both ductal and lobular morphology, and are a clear example of intratumour morphological heterogeneity. It is hypothesised that these different components evolve from a common ancestor and diverge following deregulation of the E-cadherin complex. To address this hypothesis, a cohort of 82 MDLs was studied for clinical, morphological and molecular features (Chapter 4). Key findings include: i) MDLs more frequently co-exist with ductal carcinoma in situ (DCIS) than lobular carcinoma in situ (LCIS); ii) the E-cadherin-catenin complex was often normal in the ductal component but deregulated in the lobular component; iii) E-cadherin deregulation was different to that seen in classic ILC, which are typically completely negative for this marker, not aberrant; iv) Epithelial to mesenchymal transition marker expression was not associated with E-cadherin deregulation. Exome sequencing was performed to investigate clonal relationships between the different intratumour morphologies, and identify iii mechanisms underlying the change from a 'ductal' to a more infiltrative 'lobular' growth pattern. Preliminary analysis revealed that i) all morphological components within a case are clonally related; ii) divergence of the morphological components may occur early during tumour evolution (where there are both DCIS and LCIS present) or later during tumour progression (cases with only DCIS detectible); and iii) mutations were identi...

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Prognostic significance of RACGAP1 mRNA expression in high-risk early breast cancer: a study in primary tumors of breast cancer patients participating in a randomized Hellenic Cooperative Oncology Group trial

Cited by 48 publications

References 35 publications

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

Clinical significance of RacGAP1 expression at the invasive front of gastric cancer

RacGAP1 Is a Novel Downstream Effector of E2F7-Dependent Resistance to Doxorubicin and Is Prognostic for Overall Survival in Squamous Cell Carcinoma

Intratumour heterogeneity in the development and progression of breast cancer

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