Showing papers by "Saraswati Sukumar published in 1997"

Telomerase activity: a marker to distinguish follicular thyroid adenoma from carcinoma.

Abstract: The inability to distinguish microinvasive follicular thyroid cancer from benign follicular tumors preoperatively presents an important surgical dilemma. We examined 44 follicular tumors and found telomerase activity in all 11 follicular carcinomas and in 8 of 33 benign follicular tumors. It was undetectable in 22 normal thyroid tissues adjacent to the tumors. Telomerase activity may thus provide a diagnostic marker distinguishing benign from malignant follicular thyroid tumors. The ability to identify invasive follicular thyroid tumors could avert over 14,000 thyroidectomies annually in the United States, thereby significantly decreasing morbidity and health care costs.

Altered WAF1 genes do not play a role in abnormal cell cycle regulation in breast cancers lacking p53 mutations.

Abstract: Seventy-five to 80% of breast cancers are negative for p53 gene mutations. We have investigated the possibility that altered WAF1 genes provide an alternative mode of cell cycle disruption in these tumors. DNA from a total of 85 primary breast tumors and cell lines from both the United States and Australia were examined for WAF1 and p53 mutations. With the exception of one primary tumor containing the polymorphic codon 31 (AGC-->AGA), no missense mutations in the WAF1 gene were found in 33 primary tumors or in the 19 cell lines from the United States. By contrast, 2 of 33 tumors from Australia contained tumor-specific missense mutations in the WAF1 gene, while an additional six cases contained the AGC-->AGA polymorphic 31st codon in the WAF1 gene. The p53 mutation frequency in the Australian cohort (18%) was found to be similar to that reported by us (Glebov et al., Cancer Res., 54: 3703-3709, 1994; Runnebaum et al., Proc. Natl. Acad. Sci. USA, 88: 10657-10661, 1991) in the tumors of United States patients (13%) with sporadic breast cancer. Thus, mutations in the WAF1 gene are rare in tumors with or without p53 mutations, suggesting that except in a minor population of breast cancer patients of Caucasian origin, cell cycle dysregulation by mutated p53 or WAF1 genes may not contribute to breast tumor initiation or progression.

Telomerase Activity in the Normal and Neoplastic Rat Mammary Gland

Abstract: The 1-methyl-1-nitrosourea-induced rat mammary tumor model system is well studied, reproducible, and widely used. We have investigated whether these tumors possess higher telomerase activity than normal mammary tissue. Using the telomeric repeat amplification protocol assay, we found significantly higher telomerase activity in 36 mammary carcinomas than in 72 mammary glands of virgin rats. The level of telomerase activity in virgin rats was unaffected by strain, age, stage of the estrous cycle, or ovariectomy. However, mammary glands obtained from pregnant rats exhibited telomerase activity comparable to that found in the tumors, possibly reflecting the high epithelial content of these tissues. Indeed, isolated epithelial cells from virgin and pregnant mammary glands and from carcinomas had similar telomerase activities. Thus, telomerase activity is constitutive in the rat mammary epithelium and is not a unique characteristic of malignant transformation in this tissue. These results underscore the importance of attributing biochemical properties to specific cell types in a tissue, a situation not paralleled in the interpretation of data from in vitro models.

Alterations in the Ha-ras-1 and the p53 pathway genes in the progression of N-methyl-N-nitrosourea-induced rat mammary tumors.

Abstract: Well-differentiated mammary carcinomas carrying mutated Ha-ras-1 oncogenes arise frequently in pubescent rats exposed to the direct-acting methylating agent N-methyl-N-nitrosourea (MNU). When these tumors are serially transplanted, they acquire more aggressive phenotypes. To determine the genetic alterations underlying local invasion, hormone independence, and metastasis, we studied alterations in the Ha-ras-1, p53, and mdm2 genes in successive generations of tumors passaged in intact or ovariectomized rats. Although previous studies have shown that selective amplification of the mutant Ha-ras-1 allele correlates strongly with the acquisition of hormone independence, we found that the acquisition of an invasive phenotype did not depend on mutational activation or amplification of Ha-ras-1. Mutations in the p53 gene were rare. Of a total of 120 primary, locally invasive, hormone-independent, and metastatic tumors tested for mutations in exons 4-9 of the p53 gene, only one mutation was detected in the later passages of an invasive tumor line. No gross gene alteration or amplification was seen in mdm2, a negative regulator of p53 transcription. Thus, the p53 gene is an infrequent mutational target, and amplification of the mdm2 gene does not appear to play a role in initiation or progression of rat mammary tumorigenesis.