Activated Src Protein Tyrosine Kinase Is Overexpressed in Late-Stage Human Ovarian Cancers

Wiener, Jon R.; Windham, T. Christopher; Estrella, Verónica; Parikh, Nila U.; Thall, Peter F.; Deavers, Michael T.; Bast, Robert C.; Mills, Gordon B.; Gallick, Gary E.

doi:10.1006/gyno.2002.6851

Cited by 166 publications

(109 citation statements)

References 17 publications

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“…Compared with adjacent normal tissues, elevated Src expression and/or activity has been reported in a wide range of tumour types, including breast cancer (Verbeek et al, 1996) and in many of these tissues, an increase in Src activity correlates with disease stage or malignant potential (Aligayer et al, 2002;Weiner et al, 2003). Tumour cell lines possessing elevated Src activity are often highly metastatic, displaying an increased capacity for migration and invasion in vitro (Mao et al, 1997;Jackson et al, 2000;Slack et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

et al. 2008

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Elevated c-Src protein expression has been shown in breast cancer and in vitro evidence suggests a role in endocrine resistance. To investigate whether c-Src is involved in endocrine resistance, we examined the expression of both total and activated c-Src in human breast cancer specimens from a cohort of oestrogen receptor (ER)-positive tamoxifen-treated breast cancer patients. Tissue microarray technology was employed to analyse 262 tumour specimens taken before tamoxifen treatment. Immunohistochemistry using total c-Src and activated c-Src antibodies was performed. Kaplan -Meier survival curves were constructed and log-rank test were performed. High level of nuclear activated Src was significantly associated with improved overall survival (P ¼ 0.047) and lower recurrence rates on tamoxifen (P ¼ 0.02). Improved patient outcome was only seen with activated Src in the nucleus. Nuclear activated Src expression was significantly associated with node-negative disease and a lower NPI (Po0.05). On subgroup analysis, only ER-positive/progesterone receptor (PgR)-positive tumours were associated with improved survival (P ¼ 0.004). This shows that c-Src activity is increased in breast cancer and that activated Src within the nucleus of ER-positive tumours predicts an improved outcome. In ER/PgR-positive disease, activated Src kinase does not appear to be involved in de novo endocrine resistance. Further study is required in ER-negative breast cancer as this may represent a cohort in which it is associated with poor outcome.

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Section: Discussionmentioning

confidence: 99%

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

et al. 2008

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“…Interactions with activated EGFR (Tice et al, 1999), HER2 (Muthuswamy et al, 1994), fibroblast growth factor receptor (Landgren et al, 1995), or hepatocyte growth factor (Mao et al, 1997) can result in Src activation, most likely by disrupting the intramolecular interactions that hold Src in a closed and inactive configuration (Thomas and Brugge, 1997). Importantly, aberrant expression and activation of the SFKs have been described in human ovarian cancer cell lines (Budde et al, 1994) and clinical samples (Wiener et al, 2003). A recent study used gene expression signatures that define the status of Src signalling pathways to predict the probability of Src pathway activation in 119 patients with ovarian cancer (Dressman et al, 2007).…”

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confidence: 99%

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Glas

Dering

et al. 2009

Br J Cancer

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BACKGROUND: Here, we explore the therapeutic potential of dasatinib, a small-molecule inhibitor that targets multiple cytosolic and membrane-bound tyrosine kinases, including members of the Src kinase family, EphA2, and focal adhesion kinase for the treatment of ovarian cancer. METHODS: We examined the effects of dasatinib on proliferation, invasion, apoptosis, cell-cycle arrest, and kinase activity using a panel of 34 established human ovarian cancer cell lines. Molecular markers for response prediction were studied using gene expression profiling. Multiple drug effect/combination index (CI) isobologram analysis was used to study the interactions with chemotherapeutic drugs. RESULTS: Concentration-dependent anti-proliferative effects of dasatinib were seen in all ovarian cancer cell lines tested, but varied significantly between individual cell lines with up to a 3 log-fold difference in the IC 50 values (IC 50 range: 0.001 -11.3 mmol l À1 ). Dasatinib significantly inhibited invasion, and induced cell apoptosis, but less cell-cycle arrest. At a wide range of clinically achievable drug concentrations, additive and synergistic interactions were observed for dasatinib plus carboplatin (mean CI values, range: 0.73 -1.11) or paclitaxel (mean CI values, range: 0.76 -1.05). In this study, 24 out of 34 (71%) representative ovarian cancer cell lines were highly sensitive to dasatinib, compared with only 8 out of 39 (21%) representative breast cancer cell lines previously reported. Cell lines with high expression of Yes, Lyn, Eph2A, caveolin-1 and 2, moesin, annexin-1, and uPA were particularly sensitive to dasatinib. CONCLUSIONS: These data provide a clear biological rationale to test dasatinib as a single agent or in combination with chemotherapy in patients with ovarian cancer.

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“…In epithelial ovarian carcinoma, numerous studies have revealed different patterns of genetic change. These include activation of oncogenes (K-ras, HER-2, Src, c-myc, AKT2, PIK3CA and STK/BTAK) through amplification, translocation, or mutation (Slamon et al, 1989;Enomoto et al, 1991;Tashiro et al, 1992;Bellacosa et al, 1995;Zhou et al, 1998;Shayesteh et al, 1999;Wiener et al, 2003), as well as inactivation of tumour suppressor genes (p53, PTEN, WT1, BRCA 1, NOEY2 and WWOX) through homozygous deletion, double mutations, or a combination of mutation and loss of heterozygosity or promotor methylation (Fujita et al, 1995;Obata et al, 1998;Yu et al, 1999;Schorge et al, 2000;Paige et al, 2001;McCoy et al, 2003). Although such genetic changes have long been identified using ovarian carcinoma tissues or cell lines, the early molecular changes in ovarian carcinogenesis have not been fully clarified.…”

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confidence: 99%

Establishment of an immortalised human ovarian surface epithelial cell line without chromosomal instability

et al. 2005

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Epithelial ovarian carcinoma is thought to derive from ovarian surface epithelium (OSE). The black box of the early molecular changes in ovarian carcinogenesis is being interpreted by the development of experimental systems employing immortalised human OSE cells. However, the existing cell lines of the OSE cells have limited utility due to chromosomal instability. Our goal was to establish new immortalised human OSE cells that retain the original characteristics of the primary cells without chromosomal alterations. Using primary human OSE cells obtained from a postmenopausal patient with endometrial cancer, five cell lines ('HOSE1' lines) were newly established by infection with retroviral expression vectors containing type 16 human papillomavirus (HPV-16) E6, E7, a variant E6 (E6D151), and Bmi1 polycomb gene, in combination with telomerase reverse transcriptase (hTERT). Consequently, five HOSE1s cell lines, HOSE1s-E6/hTERT, -E7/hTERT, -E6/E7/hTERT, -E6D151/E7/hTERT, and -E6D151/Bmi1/hTERT, grew beyond the population doubling number of 200. These cell lines, except for HOSE1-E6/hTERT, essentially showed the original features of the primary human OSE cells. Of them, HOSE1-E7/hTERT preserved diploidy in a kariotype analysis, and did not show transformed phenotypes in anchorage-independent growth and tumour formation. Thus, HOSE1-E7/hTERT may provide a novel model system with which to investigate the mechanisms of early molecular changes.

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Activated Src Protein Tyrosine Kinase Is Overexpressed in Late-Stage Human Ovarian Cancers

Cited by 166 publications

References 17 publications

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Phosphorylated c-Src in the nucleus is associated with improved patient outcome in ER-positive breast cancer

Activity of the multikinase inhibitor dasatinib against ovarian cancer cells

Establishment of an immortalised human ovarian surface epithelial cell line without chromosomal instability

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