Regulation of BRCA1 and BRCA2 transcript in response to cisplatin, adriamycin, taxol and ionising radiation is correlated to p53 functional status in ovarian cancer cell lines.

Recent studies suggest that BRCA1 and BRCA2 expression, in response to cytotoxic agents, may be dependent on p53 status. To investigate this possibility, we quantified their transcripts in ovarian cancer cells, PA1 (wild-type p53), CaOV-3 (mutated p53) and SKOV-3 (null p53) exposed to four cytotoxic agents. In PA1, taxol and cisplatin had no effect, while adriamycin and ionising radiation (IR) induced both genes.

BRCA1 and BRCA2 protein expressions in an ovotestis of a 46, XX true hermaphrodite.

BRCA1 and BRCA2 breast cancer susceptibility genes encode proteins, the normal cellular functions of which are complex and multiple, and germ-line mutations in individuals predispose both to breast and to ovarian cancer. There is nevertheless substantial evidence linking BRCA1 and BRCA2 to homologous recombination and DNA repair, to transcriptional control and to tissue proliferation. There is controversy regarding the localization of BRCA1 and BRCA2 proteins to either nucleus or cytoplasm and whether the expression is present in premeiotic germ cells or can still be expressed in mitotic spermatogonia.

Brca1 and Brca2 protein expression patterns in different tissues of murine origin.

We have analyzed by immunohistochemistry Brca1 and Brca2 protein expression in mouse during embryonic development, in adult tissues, and during postnatal mammary gland development. Our observations confirm previous localization of Brca1 and Brca2 mRNA on frozen sections by in situ hybridization, and demonstrate that Brca1 and Brca2 proteins are expressed in rapidly proliferating cell types undergoing differentiation. These results imply that Brca1 and Brca2 proteins are involved in the process of proliferation and differentiation in multiple tissues, notably in the mammary gland during pregnancy and lactation.

[p53 activation by PI-3K family kinases after DNA double-strand breaks].

p53 plays a central role in the cellular response to DNA double-strand breaks (DSBs), and to DNA damage in general. The protein kinases ATM, ATR and DNA-PK detect DSBs and transmit this information to p53 by phosphorylation. This phosphorylation dissociates p53 from its negative regulator, mdm2.

Cyclosporine A inhibition of prolactin-dependent up-regulation of BRCA1 protein expression in human breast cell lines.

Background: Previously, we reported experimental evidence that BRCA1, breast and ovarian cancer susceptibility gene is up-regulated in response to Prolactin stimulation. In this work, we studied the effects of Cyclosporine A and the competition with Prolactin on BRCA1 protein expression in vitro.

Methods: The expression of BRCA1 was monitored in a human breast cancer cell line (MCF7) by comparison with a normal breast epithelial one (MCF10a) treated with Cyclosporine A and ovine Prolactin.

Real-time PCR quantification of full-length and exon 11 spliced BRCA1 transcripts in human breast cancer cell lines.

Germline alterations of the BRCA1 tumor suppressor gene have been implicated at least in half of familial breast cancers. Nevertheless, in sporadic breast cancer no mutation of this gene has been characterized to date. In sporadic breast tumors, other BRCA1 gene loss of function mechanisms, such as down-regulation of gene expression, have been suggested.

Antitumoral effect of interleukin-12-secreting fibroblasts in a mouse model of ovarian cancer: implications for the use of ovarian cancer biopsy-derived fibroblasts as a vehicle for regional gene therapy.

Fibroblasts can easily be cultured from human solid ovarian tumor biopsies and are readily transfected using retroviral vectors. To test the feasibility of using these cells as a vehicle for regional, intraperitoneal (i.p.

BRCA2 protein expression in sporadic breast carcinoma with or without allelic loss of BRCA2.

To elucidate the cellular role of BRCA2 in sporadic breast tumors, we studied the cellular localization and the expression of BRCA2 in carcinomas presenting or not allelic loss of BRCA2. The breast tumors were first classified with or without allelic loss of BRCA2 and then immunohistochemical staining was performed on tumors and matched normal tissues using antibodies raised against BRCA2. We showed that BRCA2 is found either in the nucleus or in perinuclear compartments such as the endoplasmic reticulum and the Golgi vesicles.

The pathology of familial breast cancer: histological features of cancers in families not attributable to mutations in BRCA1 or BRCA2.

Breast cancers arising in carriers of mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, differ histologically from each other and from breast cancers unselected for a family history. However, a substantial proportion of families with multiple cases of breast cancer is not attributable to these two genes (non-BRCA1/2 families). We have now characterized the pathology of 82 breast cancers from non-BRCA1/2 families.

Specific H-Ras minisatellite alleles in breast cancer susceptibility.

Mutations in BRCA1 and BRCA2 genes account for the majority of familial aggregation of breast and ovarian cancers but other common genes in the population with low penetrance should be also involved in susceptibility to breast cancer. The H-ras minisatellite, located downstream of H-ras oncogene, is considered to be a likely candidate. Previous findings have estimated that as many as 1 in 11 cancers of the breast might be attributed to this region, but other studies observed inconsistent results.

Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review).

Ovarian cancer remains the leading cause of death from gynecologic malignancy in Western countries. This cancer results from a succession of genetic alterations involving oncogenes and tumor suppressor genes which have a critical role in normal cell growth regulation. Mutations and/or overexpression of three oncogenes, HER-2/neu, c-myc and K-ras, and of the tumor suppressor gene p53, have frequently been observed in sporadic ovarian cancer.

Allelic imbalance at NBS1 is frequent in both proximal and distal colorectal carcinoma.

Nijmegen breakage syndrome (NBS) is a hereditary disorder involving chromosomal instability, cancer risk and radiosensitivity. NBS carriers have an increased risk of cancer, though the significance of mutations in the NBS1 gene in sporadic cancer has not yet been investigated. Because the loss of NBS1 is associated with increased chromosomal re-arrangements, and tumors of the colon are particularly prone to chromosomal anomalies, we have begun to study the NBS1 locus in colorectal cancer (CRC).

Four years analysis of cancer genetic clinics activity in France from 1994 to 1997: a survey on 801 patients. French Cooperative Network/Groupe Génétique et Cancer de la Fédération Nationale des Centres de Lutte Contre le Cancer.

Aim: In order to evaluate the characteristics and the evolution of cancer genetics activity in France, a survey was conducted at the national level during a period of 4 years from 1994 to 1997 through the French Cooperative Network, a multidisciplinary group formed to investigate inherited tumors.

Method: A questionnaire was sent to all the 29 French non-specialized cancer genetic clinics to evaluate activity during a period of 4 consecutive weeks each year from 1994 to 1997. Items concerning the cancer genetic clinics, the consultees and the types of consultation were explored.

High incidence of cancer in a family segregating a mutation of the ATM gene: possible role of ATM heterozygosity in cancer.

ATM mutations predispose cells to malignancy by promoting chromosomal instability. We have identified a family with multiple cancers that segregates a mutant allele of ATM, IVS61+2insTA, which causes skipping of exon 61 in the mRNA, as well as a previously undescribed polymorphism, IVS61+104C(54):T(46). The mutation was inherited by two sisters, one who developed breast cancer at age 39 and the second at age 44, from their mother, who developed kidney cancer at age 67.

ATM heterozygote cells exhibit intermediate levels of apoptosis in response to streptonigrin and etoposide.

Ataxia-telangiectasia (A-T) is a rare recessive disease characterised by cerebellar ataxia, immunodeficiency, sensitivity to ionising radiation and increased cancer risk. Heterozygotes have an increased risk of cancer and may comprise 1% of the population. In vitro, A-T heterozygote cell lines show radiosensitivity intermediate between normal and A-T homozygotes.

[Genetic causes of male infertility].

In this review, after a brief summary of the spermatogenesis process, we present some genetic causes of male infertility at chromosome and gene level, known at present. Even though knowledge has greatly increased, in 15% of cases, we still do not know the infertility mechanism. The genotype-phenotype relationship remain ambiguous because of the diversity of the implicated mechanisms and their interactions.

Screening for microdeletions on the long arm of chromosome Y in 53 infertile men.

About 30% of couple infertilities are of male origin. They appear in some cases de novo and are considered idiopathic. The aim of our work was to evaluate, in these cases, the prevalence of microdeletions of the long arm of chromosome Y, within the AZF a, b and c regions using molecular biology techniques.

European multicenter study on LOH of APOC3 at 11q23 in 766 breast cancer patients: relation to clinical variables. Breast Cancer Somatic Genetics Consortium.

High frequencies of loss of heterozygosity (LOH) in chromosome 11q22-qter have been observed in various malignancies, including breast cancer. Previous studies on breast carcinomas by Winqvist et al (Cancer Res 55: 2660-2664) have indicated that a survival factor gene is located in band 11q23, and that the highly informative microsatellite polymorphism at the APOC3 locus would be a suitable tool to perform more extensive LOH studies. In this European multicentre study, we have examined the occurrence of APOC3 LOH and evaluated the effect of LOH of this chromosomal subregion on the clinical behaviour of the disease in a cohort of 766 breast cancer patients in more detail.

[Mutation by deletion-insertion in BRCA-1 gene in three unrelated French breast/ovarian cancer families: possible implication of a mobile element].

A new type of mutation by deletion-insertion in BRCA-1 gene is found in three unrelated French breast/ovarian cancer families. Surprisingly, deletion and insertion occurred at the same nucleotide position at the end of exon 11 (3958del5ins4), thus generating a truncated protein. This original mutation consists in a deletion of 5 bp (CTCAG) and in an insertion of 4 different bp (AGGC).

Prolactin-dependent up-regulation of BRCA1 expression in human breast cancer cell lines.

We report experimental evidence that BRCA1, a breast and ovarian cancer susceptibility gene, is up-regulated in response to prolactin (PRL) stimulation. Expression of the BRCA1 gene was monitored in 2 human breast cancer cell lines (MCF-7 and T-47D) and in the normal mammary epithelial cell line MCF10a. Using competitive RT-PCR, we have shown that PRL induced an increase in BRCA1 mRNA level in MCF-7 and T-47D cell lines at a dose resulting in the maximal enhancement of cell proliferation.