Incidence of p53 and Ha-ras gene mutations in chemically induced rat mammary carcinomas

Kito, Katsumi; Kihana, Toshimasa; Sugita, Atsuro; Murao, Shinichi; Akehi, Shun; Sato, Mariko; Tachibana, M.; Kimura, Shigeru; Ueda, Norifumi

doi:10.1002/(sici)1098-2744(199610)17:2<78::aid-mc4>3.0.co;2-p

Cited by 43 publications

(28 citation statements)

References 35 publications

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“…These mutations have been found in cancer of the bladder (24), laryngeal carcinoma (25), soft-tissue malignant fibrous histiocytomas (26), chemically induced rat mammary carcinomas (27), and bronchogenic carcinoma (28). It is of interest that thyroid tumours induced by chemical carcinogens in rats involve activation of Ha-ras (21).…”

Section: Discussionmentioning

confidence: 99%

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers

Bouras

Bertholon²,

Dutrieux-Berger³

et al. 1998

European Journal of Endocrinology

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Structural alterations to proto-oncogene sequences may be involved in the pathogenesis of human thyroid neoplasms. We studied 128 thyroid tumours (35 benign and 93 malignant) for ras gene point mutations in three different codons (12, 13 and 61) using a restriction fragment length polymorphism technique and direct sequencing of double-stranded DNA on polymerase chain-reaction-amplified tumour DNA. We found a high frequency of ras mutation for the Ha-ras codon 12 in follicular adenomas (7 of 35), particularly in atypical adenomas (5 of 17), in follicular carcinomas (6 of 19), with a high percentage for Hü rthle cell carcinomas (6 of 11), and in papillary carcinomas (4 of 66). Point mutations for other ras genes in different codons studied were weak to absent. No mutation was found in undifferentiated carcinomas (n ¼ 8). The predominant amino acid substitution both in the adenomas and in the differentiated tumours was glycine to valine (GGC to GTC) at position 12 of the Ha-ras gene.Our results obtained on a large series confirm the frequent occurrence of Ha-ras codon 12 gene mutations both in adenomas and in carcinomas. The frequency of ras mutations is linked to the geographical origin of the population studied, and varies (0-85%) from one cancer type to another according to published data. Therefore, these mutations are merely an expression of cellular transformation.

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Section: Discussionmentioning

confidence: 99%

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers

Bouras

Bertholon²,

Dutrieux-Berger³

et al. 1998

European Journal of Endocrinology

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“…Our recent studies demonstrate that progestin-stimulated expression of VEGF only occurs in progesterone receptor (PR)-positive cells that express mutant p53 . In model rodent systems (e.g., DMBA-induced mammary tumors in mice), p53 mutations in the pre-neoplastic lesions of the mammary gland are frequent (Jerry et al 1993), though frank tumors seem to develop from the cells that retain their wild-type p53 status (Kito et al 1996). However, it is not yet known whether medroxyprogesterone acetate (MPA)-accelerated DMBA-induced tumors in rodents express mutant p53 as a result of potential proliferative effects of MPA on both wild-type and mutant p53 expressing cells in the pre-neoplastic lesions.…”

Section: Introductionmentioning

confidence: 99%

Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague–Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study

Benakanakere

Besch‐Williford²,

Ellersieck³

et al. 2009

Endocrine-Related Cancer

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Abstractp53 Reactivation and induction of massive apoptosis (PRIMA-1) is a small-molecule compound that reactivates mutant p53, restoring its normal tumor suppressor function. PRIMA-1 effectively suppresses the growth of homogeneous p53-deficient tumor xenografts in immunosuppressed mice; however, the ability of PRIMA-1 to suppress the growth of mammary tumors in rodents and other species is not well characterized. Here, we examined the ability of PRIMA-1 to suppress the growth of 7,12-dimethylbenz[a]anthracene (DMBA)-induced and progestin-accelerated DMBAinduced mammary tumors in Sprague-Dawley rats. Mammary tumors were induced in female rats with DMBA or DMBA plus progestin treatment. After tumors had reached 5-25 mm 2 in size, PRIMA-1 was administered twice a day for 3 days via tail vein injection (20 or 50 mg/kg). Tumor size was monitored every day following PRIMA-1 for at least 15 days prior to killing. PRIMA-1 caused regression of w40% of progestin-accelerated DMBA-induced mammary tumors, but did not induce regression of native non-progestin-accelerated DMBA-induced tumors. Importantly, PRIMA-1 also suppressed the emergence of any new progestin-accelerated tumors in this model. Immunological studies with an antibody that selectively reacts with mutant p53 suggested that none of the native DMBA-induced tumors expressed mutant p53. By contrast, six out of eight progestin-accelerated DMBA-induced tumors stained for mutant p53 protein. In PRIMA-1-treated tumor-bearing rats, tumor regression correlated with conversion of mutant to wild-type p53 conformation, reduced expression of vascular endothelial growth factor and estrogen receptor, lack of blood vessel perfusion, increased expression of p21, and massively increased expression of anti-angiogenic protein, secreted protein acidic and rich in cysteine. These pre-clinical results suggest that PRIMA-1, as a single agent or in combination with other anti-cancer compounds, has potential as a novel chemotherapeutic treatment for progestin-accelerated human breast cancer.

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“…In mammary tumors induced by chemical carcinogens (DMBA or NMU), the ras pathways are mutated preferentially and rarely result in altered expression or mutation of p53 (McKenzie et al, 1997;Qing et al, 1997;Kito et al, 1996;Kumar et al, 1990;Jerry et al, 1994). Likewise, mammary tumors that arise from targeted overexpression of dominant-acting oncogenes do not appear to require disruption of the p53 pathway (Ritland et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development

et al. 2000

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Although alterations in the p53 tumor suppressor gene are detected frequently in human breast cancers, mammary tumors are observed infrequently in p53 null mice. This has led to the suggestion that absence of p53 alone is not sucient for induction of mammary tumors. However, early death of p53 null mice from thymic lymphomas may obscure tumor phenotypes that would develop later. Therefore, p53null mammary epithelium was transplanted into cleared mammary fat pads of wild type p53 BALB/c hosts to allow long-term analysis of mammary tumor phenotypes. Five treatments were compared for their eects on tumor incidence in hosts bearing transplants of p53 null vs p53 wt mammary transplants for each treatment group were 62% vs 0%, 100% vs 0%, 68% vs 0%, 60% vs 4% and 91% vs 14%, respectively. The mammary tumors that developed in the p53 null mammary epithelium were all adenocarcinomas and were frequently aneuploid. These data demonstrate that the absence of p53 is sucient to cause development of mammary tumors and that hormonal stimulation enhances the tumorigenicity of p53 null mammary epithelium to a greater extent than DMBA exposure alone. This model provides an in situ approach to examine the molecular basis for the role of p53 in the regulation of mammary tumorigenesis.

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Incidence of p53 and Ha-ras gene mutations in chemically induced rat mammary carcinomas

Cited by 43 publications

References 35 publications

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers

Variability of Ha-ras (codon 12) proto-oncogene mutations in diverse thyroid cancers

Regression of progestin-accelerated 7,12-dimethylbenz[a]anthracene-induced mammary tumors in Sprague–Dawley rats by p53 reactivation and induction of massive apoptosis: a pilot study

A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development

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