Estimating genomic instability mediated by Alu retroelements in breast cancer

Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)

Association of matrix metalloproteinase-8 gene variation with breast cancer prognosis

Animal and cell studies indicate an inhibitory effect of matrix metalloproteinase-8 (MMP8) on tumorigenesis and metastasis. We investigated whether MMP8 gene variation was associated with breast cancer metastasis and prognosis in humans. We first studied nine tagging single nucleotide polymorphisms (SNP) in the MMP8 gene in 140 clinically and pathologically well-characterized breast cancer patients. Four of the SNPs were found to be associated with lymph node metastasis, the most pronounced being a promoter SNP (rs11225395) with its minor allele (T) associating with reduced susceptibility to lymph node metastasis (P = 0.02). This SNP was further evaluated for association with cancer relapse and survival among a cohort of similar to 1,100 breast cancer patients who had been followed for cancer recurrence and mortality for a median of 7.1 years. The T allele was associated with reduced cancer relapse and greater survival, particularly among patients with earlier stage cancer. Among patients of tumor-node-metastasis stage 0 to 11, the adjusted hazard ratio of disease-free survival was 0.7 [95% confidence interval (95% CI), 0.5-0.9] for patients carrying T allele compared with those homozygous for the C allele (P = 0.02). In vitro experiments showed that the T allele had higher promoter activity than the C allele in breast cancer cells. Electrophoretic mobility shift assays showed binding of nuclear proteins to the DNA sequence at the SNP site of the T allele but not that of the C allele. The data suggest that MMP8 gene variation may influence breast cancer prognosis and support the notion that MMP8 has an inhibitory effect on cancer metastasis.

Profile of thyroid hormones in breast cancer patients

Estrogen involvement in breast cancer has been established; however, the association between breast cancer and thyroid diseases is controversial. Estrogen-like effects of thyroid hormone on breast cancer cell growth in culture have been reported. The objective of the present study was to determine the profile of thyroid hormones in breast cancer patients. Serum aliquots from 26 patients with breast cancer ranging in age from 30 to 85 years and age-matched normal controls (N = 22) were analyzed for free triiodothyronine (T3F), free thyroxine (T4F), thyroid-stimulating hormone (TSH), antiperoxidase antibody (TPO), and estradiol (E2). Estrogen receptor ß (ERß) was determined in tumor tissues by immunohistochemistry. Thyroid disease incidence was higher in patients than in controls (58 vs 18%, P < 0.05). Subclinical hyperthyroidism was the most frequent disorder in patients (31%); hypothyroidism (8%) and positive anti-TPO antibodies (19%) were also found. Subclinical hypothyroidism was the only dysfunction (18%) found in controls. Hyperthyroidism was associated with postmenopausal patients, as shown by significantly higher mean T3 and T4 values and lower TSH levels in this group of breast cancer patients than in controls. The majority of positive ERß tumors were clustered in the postmenopausal patients and all cases presenting subclinical hyperthyroidism in this subgroup concomitantly exhibited Erß-positive tumors. Subclinical hyperthyroidism was present in only one of 6 premenopausal patients. We show here that postmenopausal breast cancer patients have a significantly increased thyroid hormone/E2 ratio (P < 0.05), suggesting a possible tumor growth-promoting effect caused by this misbalance.

Production and body composition traits of broilers in relation to breast weight evaluated by path analysis

O peso do peito possui grande importância econômica na indústria de frangos, podendo estar associado a outras variáveis passíveis de seleção. Estimaram-se correlações fenotípicas entre características de desempenho (peso vivo aos 7, 28 dias e ao abate e profundidade de músculo peitoral por ultra-sonografia), carcaça (peso eviscerado e de pernas) e composição corporal (peso do coração, do fígado e da gordura abdominal), em uma linhagem de frangos, e quantificou-se a influência direta e indireta destas variáveis sobre o peso do peito. Para tanto, utilizou-se a análise de trilha, desdobrando-se a matriz de correlações parciais em coeficientes que forneceram a influência direta de uma variável sobre a outra, independentemente das demais. A manutenção das variáveis peso vivo ao abate e peso eviscerado na matriz de correlações pode ser prejudicial à análise estatística que envolve os sistemas de equações normais, como a análise de trilha, devido à multicolinearidade observada. O peso vivo ao abate e a profundidade do músculo peitoral por ultra-sonografia apresentaram efeitos diretos importantes sobre o peso de peito e foram identificadas como as principais responsáveis pela magnitude dos coeficientes de correlação obtidos. Assim, uma pré-seleção individual para estas características pode favorecer um aumento no peso de peito nesta linhagem, se mantidas as condições ambientais de criação dos frangos, uma vez que o peso vivo ao abate e a profundidade de músculo peitoral por ultra-sonografia afetam fenotipicamente e diretamente o peso de peito.

DUCTAL CARCINOMA IN-SITU OF THE BREAST - HISTOLOGIC CATEGORIZATION AND ITS RELATIONSHIP TO PLOIDY AND IMMUNOHISTOCHEMICAL EXPRESSION OF HORMONE RECEPTORS, P53, AND C-ERBB-2 PROTEIN

Background. Ductal carcinoma in situ (DCIS) of the breast has been diagnosed increasingly since the advent of mammography. However, the natural history of these lesions remains uncertain. Ductal carcinoma in situ of the breast does not represent a single entity but a heterogeneous group with histologic and clinical differences. The histologic subtype of DCIS seems to have an influence on its biologic behavior, but there are few studies correlating subtype with biologic markers.Methods. The authors studied a consecutive series of 40 cases of DCIS and after its histologic categorization verified its relationship with ploidy using image analysis and analyzing estrogen receptor (ER), progesterone receptor (PR), p53 and c-erbB-2 expression using immunohistochemistry.Results. The three groups proposed according to the grade of malignancy were correlated significantly with some of the additional parameters studied, including aneuploidy and c-erB-2 expression. Aneuploidy was detected in 77.5% of cases of DCIS mainly in high and intermediate grade subtypes (100% and 80% vs. 35.7% in low grade) whereas immunoreactivity for c-erbB-2 was detected in 45% of cases of DCIS mainly in the high grade group. Expression of ER and PR were observed frequently in this study (63.9% and 65.7% respectively), but without correlation with the histologic subtype of DCIS, although we found a somewhat significant association between high grade DCIS and lack of ER. p53 protein expression was detected in 36.8% of these cases, but no relationship between this expression and histologic subtype or grading of DCIS was found.Conclusions. These results provide further evidence for the morphologic and biologic heterogeneity of DCIS. Besides histologic classification and nuclear grading, some biologic markers such as aneuploidy and c-erbB-2 expression constitute additional criteria of high grade of malignancy.

EXPRESSION OF C-ERB B-2 PROTEIN AND DNA-PLOIDY IN BREAST CARCINOGENESIS

Objective.-to examine the c-erb B-2 expression and nuclear DNA content in samples of breast lesions to ascertain any relationship between c-erb B-2 expression and aneuploidy in the different types of proliferative breast lesions and in intraductal and invasive carcinomas.Design and Setting.-lmmunohistochemical analysis of c-erb B-2 expression and cytometric nuclear DNA assessment were performed in a series of 39 cases of intraductal hyperplasia without atypia, 7 cases of intraductal hyperplasia with atypia, 64 cases of intraductal carcinoma, and 85 cases of invasive breast carcinoma (30 of which had extensive intraductal component).Results.-Overexpression of c-erb B-2 was seen only in cases of carcinoma: 28 (43.7%) intraductal carcinomas and 15 (17.6%) invasive carcinomas. Aneuploidy was demonstrated in 3 (43.0%) cases of intraductal hyperplasia with atypia, in 54 (84.4%) cases of intraductal carcinoma, and in 63 (74.2%) cases of invasive carcinoma. All cases of intraductal hyperplasia without atypia were euploid and none expressed c-erb B-2. Among the carcinomas (intraductal and invasive) there was a strong relationship between aneuploidy and c-erb B-2 expression. In most instances, the intraductal and invasive components of the 30 invasive carcinomas with extensive intraductal component displayed similar DNA content and c-erb B-2 immunoreactivity; whenever there was a difference, the intraductal component tended to be aneuploid (five out of six cases) and c-erb B-2 positive (one case), in contrast to the respective invasive component.Conclusions.-The higher frequency of aneuploidy and c-erb B-2 expression in intraductal carcinomas in comparison with invasive carcinomas suggests there is not a linear relationship between DNA content abnormalities and neoplastic progression and that some invasive breast carcinomas evolve without an identifiable intraductal phase or are unrelated to disturbances at the c-erb B-2 locus.