Ras p21 in breast tissue: associations with pathology and cellular localisation

Going, James J.; Anderson, Thomas; Wyllie, Andrew H.

doi:10.1038/bjc.1992.9

Cited by 28 publications

(18 citation statements)

References 41 publications

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“…Elsewhere we show (Arends et al unpublished data) that these transfected cell lines have differences in their rates and aggressiveness of tumour growth in vivo that correspond to the phenomena described here in vitro, extending the previously published data (Wyllie et al, 1987) that showed that a T24-ras expressing cell line (TI) produced a higher primary tumour take-rate and a significantly higher proportion of test mice with metastasis at 14 days, compared with a c-myc expressing line (MI). There is also evidence from human pathology that expression of myc is associated with tumours with high cell turnover (Field & Spandidos, 1990), whereas ras expression or oncogenic activation is associated with cell population expansion in potentially premalignant tumours of the colon and breast, rather than acquisition of specific features of the malignant phenotype (Williams et al, 1985;Going et al, 1992). Thus, the data support the hypothesis that oncogenes such as ras and bcl-2 can suppress apoptosis (Vaux et al, 1988;Hockenbery et al, 1990;Nunez et al, 1990).…”

Section: Susceptibility To Apoptosis Reflects Availability Of Endonucsupporting

confidence: 73%

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability

Arends

Mcgregor²,

Toft³

et al. 1993

Br J Cancer

Self Cite

115

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Summary Oncogenes and oncosuppressors can derugulate cell replication in tumours, and recently have been shown to influence the probability of apoptosis. The effects of human c-myc and mutated (T24) Ha-ras oncogenes on susceptibility to apoptosis were investigated by introducting them into immortalised rat fibroblasts. The resulting family of transfectants showed closely similar measures of proliferation, but widely divergent rates of apoptosis, differing by up to fifteen-fold, that correlated inversely with population expansion rates in vitro. T24-ras transfectants with moderate or high p2lras expression showed reduced apoptosis, and this was reversed by pharmacological inhibition of membrane localisation of p2l's by mevinolin. In contrast, c-myc stimulated apoptosis, and this was further enhanced by serum deprivation. Inducibility of effector proteins represents one possible mechanism of genetic control of the susceptibility to apoptosis, and its investigation showed that c-myc was associated with expression by viable cells of latent calcium/magnesium sensitive endonuclease activity characteristic of apoptosis. In contrast, endonuclease activity was not detected in viable cells of a T24-ras transfectant expressing high levels of p2lras. Thus, there appeared to be differential regulation of susceptibility to apoptosis, positively by c-myc and negatively by activated ras, and this was associated with availability of endonuclease activity. Genetic modulation of apoptosis in human neoplasms is likely to influence net growth rate, retention of cells acquiring new mutations and response to certain chemotherapeutic agents.

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Section: Susceptibility To Apoptosis Reflects Availability Of Endonucsupporting

confidence: 73%

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability

Arends

Mcgregor²,

Toft³

et al. 1993

Br J Cancer

Self Cite

115

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“…Work by Ohuchi et al (1986) and Going et al (1992) indicates that ras p21 expression increases through the histological progression from normal breast epithelium to in situ cancer. There is little further inacrease in invasive cancer and metastases have a rather heterogeneous staining, implying that the expression of ras p21 is not required for maintenance of the transformed phenotype (Fromowitz et al, 1987).…”

Section: Relationship Between Clinicopathological Variables Andp53 Exmentioning

confidence: 99%

Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy

Archer

Eliopoulos²,

Spandidos³

et al. 1995

Br J Cancer

134

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Summary Several oncogenes and tumour-suppressor genes have been identified that may have an important role in the development of human breast carcinoma. Furthermore, some of these gene alterations may be linked to the development of invasion and subsequent metastasis. Alterations in the expression of ras p21, p53 and c-erbB-2 have all been linked to tumours with rapid cellular proliferation. but the evidence that they are of prognostic importance in patients with breast cancer is conflicting. This study explores the relationship between expression of these oncoproteins and clinical outcome in 92 patients with either locally advanced or metastatic breast cancer treated with prinmary endocrine therapy. Specimens of the primary carcinoma were available for analysis of hormone receptor, Ki67 labelling index, epidermal growth factor receptor (EGFR), c-erbB-2, p53 and ras p21. Clinical response was measured according to UICC criteria after 6 months of treatment and all patients were followed for time to progression and overall survival. As shown previously, oestrogen receptor (ER) negativity, high Ki67 labelling index and EGFR overexpression were associated with a shorter time to progression and overall survival. However, no statistically significant relationship existed between expression of ras p21, p53 or c-erbB-2 and response to treatment, time to progression or overall survival. We conclude that staining for these three oncoproteins has no role in therapeutic decision-making in patients with advanced breast cancer. The negative finding implies that while abnormal expression of these genes may have an important role in the development of breast cancer, the variations in growth characteristics of advanced breast cancer may be influenced by other factors.

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“…Inappropriate rescuing stimuli may therefore be oncogenic simply because they increase the number of cells available for mutagenesis. There are several potential examples, such as ras expression in premalignant hyperplasias of breast (Going et al, 1992) and in colorectal adenomas (Williams et al, 1985) and the constitutive bcl-2 expression of follicular lymphomas and the LMP-l-induced bcl-2 expression of drug-resistant Burkitt's lymphoma cell lines (Clark et al, 1992;Gregory et al, 1991;Henderson et al, 1991).…”

mentioning

confidence: 99%

Apoptosis (the 1992 Frank Rose Memorial Lecture)

1993

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Summary Apoptosis is a mode of cell death with characteristic structural features. These appear to result from a set of discrete cellular events that are regulated by gene expression. Oncogenesis and oncosuppressor genes are involved in this regulation. The role of c-myc is of particular interest, as it can act as a bivalent regulator, determining either cell proliferation or apoptosis, depending on whether free movement around the cell cycle is supported (by growth factors) or is limited by growth factor deprivation or treatment with other cycle-blocking agents. In vivo, c-myc expression may be associated with a 'high-turnover' state in which cell proliferation and apoptosis co-exist. Certain other oncogenes (e.g. ras, bcl-2) rescue cells from susceptibility to apoptosis and so convert this high-turnover state into rapid population expansion. One role of the oncosuppressor gene p53 may be to initiate apoptosis by causing G 1/S arrest in cells expressing c-myc. Some aspects of resistance and sensitivity to chemotherapeutic agents can be explained on the basis of movement between the population-expansion and the high-turnover states, perhaps through modulation of the expression of these and other genes.

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Ras p21 in breast tissue: associations with pathology and cellular localisation

Cited by 28 publications

References 41 publications

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability

Susceptibility to apoptosis is differentially regulated by c-myc and mutated Ha-ras oncogenes and is associated with endonuclease availability

Expression of ras p21, p53 and c-erbB-2 in advanced breast cancer and response to first line hormonal therapy

Apoptosis (the 1992 Frank Rose Memorial Lecture)

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