[Aromatase gene expression and its modifying factors in breast tumor tissue]. / Ekspressiia gena aromatazy i modifitsiruiushchie eë faktory v tkani opukholei molochnoi zhelezy.

Aromatase (CYP 19) gene expression was studied in 70 breast tumors. When RNA-dot-blot or rt-polymerase chain reaction were used expression frequency was 60.4 and 91.7%, respectively. An analysis of individual variants of non-coding exon of aromatase gene confirmed that, unlike normal mammary tissue, tumor switched from activation of exon I.4 ("sensitive" to glucocorticoids) to exons II ("sensitive" to cAMP) or I.3. This difference was relatively somewhat more pronounced in the Russian material. Direct correlation between aromatase enzymatic activity and expression of exons II and I.3 in tumor tissue appeared more significant than that of aromatase gene coding site. An evaluation of the expression of adenylate cyclase G-protein alpha-subunit genes established an inverse correlation between expression of Gi2a and exon I.3. Breast tumors with elevated basal aromatase activity were more sensitive to aromatase inhibitors (letrozole, 4-OHA) in vitro although no relationship between use of CYP19 (aromatase) 5' exon variant and in vitro inhibition of aromatase was detected. A correlation was observed between expression of aromatase gene and variants of its 5' exon, on the one hand, and age, tumor grade, steroid receptor presence and tumor lymphocytic infiltration, on the other. To summarize, local estrogen production in breast tumor tissue is regulated by a wide range of factors expression both aromatase gene influencing and its enzymatic activity, thus providing leverage on both.

[S allele of the L-myc oncogene is associated with lung cancer metastases in patients from Moldova]. / [S-allel' onkogena L-myc assotsirovan s metastazirovaniem raka lëgkikh u bol'nykh iz Moldovy]

Race is widely believed to be a factor in the relationship between S allele of L-MYC oncogene and disseminated lung cancer. In particular, the clinical significance of L-MYC genotype was demonstrated in the Japanese while the results for the white US, Australian and Norwegian cohorts were negative. The present study was concerned with distribution of L-MYC oncogene alleles in 43 patients with lung cancer and 77 healthy subjects in Moldova. L and S allele frequency in both groups were nearly identical. However, the SS genotype was registered much more frequently in patients with metastasis (10/28; 36%)(p < 0.05) than in those with localized tumor (0/12). Moreover, overall frequency of S allele was significantly higher in lung cancer patients with node involvement (35/56; 63%)(p < 0.02) than in those with localized tumors (8/24; 33%)(p < 0.02). Finally, a significant correlation was found between S allele occurrence and distant metastases (M1: 19/28; 68%; M0:26/58; 45%)(p < 0.05). Similar data were reported in Russia. (ABSTRACT TRUNCATED)

[Aromatase activity and its gene expression in tumor tissue of smokers and non-smokers with breast cancer]. / Aktivnost' aromatazy i ékspressiia eë gena v opukholevoi tkani u kuriashchikh i nekuriashchikh bol'nykh rakom molochnoi zhelezy.

Tissue was sampled from 121 tumors of the breast. The activity of aromatase (estrogen synthetase) was assessed by radiobiochemical means in 61 cases; gene expression was evaluated with the aid of polymerase chain reaction in 14 and the same--by the dot-blot procedure in 46 patients. Inveterate smokers (15 years and more) made up 16.5%. The smokers revealed a distinct tendency towards aromatase activity decreasing in tumor tissue (chiefly in menopausal patients) as well as lower intensity of aromatase gene expression assessed in terms of polymerase chain reaction. Alongside with other evidence, our finding point to long-term-smoking-related sensitivity of intratissular estrogen synthesis being higher than in general circulation. It also demonstrated local aromatization inhibition in tumor tissue, the latter being a possible mechanism which causes tumor tissue hormone sensitivity to change in smokers and affects course of disease.

[Correlation between int-2 oncogene amplification and increased tumor size in breast cancer]. / Assotsiatsiia amplifikatsii onkogena int-2 s uvelichennym razmerom opukholi pri rake molochnoi zhelezy.

Amplification of the int-2 oncogene was observed in 10 out of 78 (13%) samples of DNA isolated from cells of primary breast tumor. A clinico-morphological examination established a correlation between this molecular-genetical anomaly and tumor size: gene amplification was detected in 1 out 34 (3%) cases of breast tumor under 2 cm and in 9 out 44 (20%) tumors measuring 2 cm and more (p < 0.05). Similarly, a kind of correlation was found between gene amplification and low differentiation of breast cancer cells: enhanced copying ability of the oncogene was registered in 2 out 4 (50%) breast tumors with low cell differentiation, 8 out 69 (12%) tumors with medium cell differentiation, while it was not identified in 5 breast carcinomas with high cell differentiation (p < 0,2).

[Amplification of the erbb-2 (Her-2/NEU), erbb-1 (HER-1) and c-myc oncogenes is often combined with the deletion of the short arm of chromosome 17 in human carcinoma]. / Amplifikatsiia onkogenom erbb-2 (HER-2/NEU), erbb-1 (HER-1) i c-myc chasta sochetaetsia s deletsiei korotkogo plecha khromosomy 17 v kartsinomakh u chelovekakh.

Amplification of oncogenes erbb-2, erbb-1, c-myc and losses of heterozygosity (LOH) at chromosomes 11p (probe hras-1), 17p (probe ynz-22) and 17q (probe thh-59) were studied in 165 human tumours (60 breast, 22 ovary, 40 colorectal, 23 lung, and 20 thyroid carcinomas). The correlation (P < 0.01) between the increased copy number of mentioned oncogenes and LOH at 17p was demonstrated for tumours tested: extra copies of these oncogenes were revealed in 11 of 46 DNA specimens with LOH on ynz-22, but only in 3 of 61 without LOH. This correlation was mostly due to frequent combinations between erbb-2 amplification and 17p deletions; the incidence of increased copy number of erbb-1 and c-myc oncogenes was not high enough for final conclusions about the association of their alterations with LOH at chromosome 17p.

Amplification of HER-2(erbB-2/neu) oncogene as the most significant prognostic factor in a group of Russian breast cancer patients.

Amplification of HER-2(erbB-2/neu) oncogene was detected in 36 of 142 (25%) breast carcinomas (BC) RNA expression was examined in 42 carcinomas, in 10 of them overexpression was revealed. Amplification was matched by overexpression. No association was found between the increased number of HER-2(erbB-2/neu) copies and tumor size, lymph node involvement, stage of disease, age of onset, and estrogen and progesterone receptor level. HER-2(erbB-2/neu) amplification was shown to be of independent prognostic significance in the group of 32 BC patients with sufficient follow-up (more than 40 months). Six of 7 HER-2(erbB-2/neu) amplification-positive patients and only 2 of 25 HER-2(erbB-2/neu) amplification-negative ones relapsed (p < 0.00005).

Loss of heterozygosity at chromosome 17p is associated with HER-2 amplification and lack of nodal involvement in breast cancer.

Sixty DNA samples from breast carcinoma (BC) patients were analyzed by Southern blot to examine certain oncogene and anti-oncogene alterations. Amplification of the HER-2 oncogene was detected in 15 tumours (25%), c-myc in 2 (3%) only and HER-1 in none. Distribution of Hras-1 oncogene alleles in BC did not significantly differ from that seen in healthy donors. Not a single case of RB-1 anti-oncogene alteration and only one of p53 suppressor gene abnormality was found when appropriate cDNA copies were used as probes. With the use of DNA polymorphic markers, loss of heterozygosity (LOH) was revealed at chromosome 17p (probe YNZ-22) in 18 of 39 (46%) informative cases, at 17q (probe THH-59) in 10 of 34 (29%) and at 11p (probe Hras-1) in 8 of 30 (27%). The only significant correlation between these genetic alterations and the clinical characteristics of the tumours studied was the association of LOH at 17p with node-negative BC (p < 0.02). Also, the tendency for correlation (p < 0.2) between HER-2 amplification and loss of 17p sequences was revealed: 7 of 10 amplification-positive, but only 11 of 29 amplification-negative BC possessed LOH of YNZ-22 locus.

[Complex characteristics of the alterations of oncogenes HER-2/ERBB-2, HER-1/ERBB-1, HRAS-1, C-MYC and antioncogenes p53, RB1, as well as deletions of loci of chromosome 17 in colon carcinoma]. / Kompleksnaia kharakteristika povrezhdenii onkogenov HER-2/ERBB-2, HER-1/ERBB-1, HRAS-1, C-MYC i antionkogenov p53, RB1, a takzhe deletsii lokusov khromosomy 17 v kartsinomakh tolstoi kishki.

Abnormalities of some oncogenes, antioncogenes and losses of heterozygosity (LOH) of chromosome 11p, 17p, and 17q in colorectal carcinomas (CC) was studied. Amplification of ERBB-1/HER-1 oncogene was detected in 2 of 56 cases; ERBB-2/HER-2- in 4 of 62. There was a lack of evidence for C-MYC oncogene amplification (67 cases). LOH of chromosome 11p (HRAS-1 probe) was found in 2 of 37 informative (heterozygous) cases; such events were not accompanied by point mutations in "hot" codons (12th or 61st) in the remaining allele. Prevalence of A3 and A4 alleles of HRAS-1 oncogene (68 cases) as compared to healthy donors was noted. RB-1 (41 cases) and p53 (62 cases) suppressor genes did not show any alterations in Southern-blot analysis. LOH of chromosome 17p (YNZ-22 probe) was found in 15 of 26 heterozygous CC; 17q (THH-59 probe)--in 4 of 16. Analysis of 175th codon of p53 gene revealed only one case of mutation in 35 CC studied. Finally, we were able to detect genetic alterations in 23 of 40 (58%) CC, that were studied on each parameter using Southern-blot. We failed to find any correlation between various molecular abnormalities or clinical characteristics. The data obtained are in disagreement with the view concerning frequent involvement of p53 antioncogene in chromosome 17p deletions.

[The search for amplification of the ERBB-2 oncogene in human tumors]. / Poisk amplifikatsii onkogena ERBB-2 v opukholiakh cheloveka.

The occurrence of ERBB-2 (HER-2/NEU) oncogene amplification was studied in 203 DNA samples obtained from 175 cancer patients. Amplification of ERBB-2 oncogene was established in 14 out of 63 (22%) patients with breast cancer, 1 out of 23 cases of ovarian tumor, 1 out of 19 cases of large bowel cancer and 1 out of 27 patients with cancer of the thyroid. Patients with lung cancer (34), soft tissue sarcoma (6) and malignant melanoma (3) failed to reveal any changes in the above oncogene. A tendency was established for ERBB-2 oncogene amplification to be associated with lymph node involvement in female patients with breast cancer: amplification was observed in 9 out of 28 patients presenting with lymph node metastases and only in 5 out of 29 metastases-free cases. To summarize, ERBB-2 oncogene is fairly often activated in human tumors but a high occurrence of the gene amplification was observed in female patients with breast cancer only.