ABSTRACT
Almost half of all hereditary breast cancers (BCs) are associated with germ-line mutations in homologous recombination (HR) genes. However, the tumor phenotypes associated with different HR genes vary, making it difficult to define the role of HR in BC predisposition. To distinguish between HR-dependent and -independent features of BCs, we generated a mouse model in which an essential HR gene, Rad51c, is knocked-out specifically in epidermal tissues. Rad51c is one of the key mediators of HR and a well-known BC predisposition gene. Here, we demonstrate that deletion of Rad51c invariably requires inactivation of the Trp53 tumor suppressor (TP53 in humans) to produce mammary carcinomas in 63% of female mice. Nonetheless, loss of Rad51c shortens the latency of Trp53-deficient mouse tumors from 11 to 6 months. Remarkably, the histopathological features of Rad51c-deficient mammary carcinomas, such as expression of hormone receptors and luminal epithelial markers, faithfully recapitulate the histopathology of human RAD51C-mutated BCs. Similar to other BC models, Rad51c/p53 double-mutant mouse mammary tumors also reveal a propensity for genomic instability, but lack the focal amplification of the Met locus or distinct mutational signatures reported for other HR genes. Using the human mammary epithelial cell line MCF10A, we show that deletion of TP53 can rescue RAD51C-deficient cells from radiation-induced cellular senescence, whereas it exacerbates their centrosome amplification and nuclear abnormalities. Altogether, our data indicate that a trend for genomic instability and inactivation of Trp53 are common features of HR-mediated BCs, whereas histopathology and somatic mutation patterns are specific for different HR genes.
Subject(s)
Breast Neoplasms/genetics , Mammary Neoplasms, Animal/genetics , Rad51 Recombinase/genetics , Tumor Suppressor Protein p53/genetics , Animals , Breast Neoplasms/pathology , DNA-Binding Proteins , Disease Models, Animal , Female , Gene Deletion , Germ-Line Mutation/genetics , Homologous Recombination/genetics , Humans , Mammary Neoplasms, Animal/pathology , Mice , Mice, KnockoutABSTRACT
The aim of this study was to identify the specific somatostatin receptors expressed by several tumors, utilizing 111In-octreotide, a long acting somatostatin analogue. We studied two different groups of patients: the first group was composed of 21 patients suffering from different pituitary adenomas, while the second group consisted of 12 patients affected by several different neoplasms. In vivo scintigraphy showed pentetreotide receptors only in large GH-secreting adenomas and several macroadenomas. Concerning the endocrine activity of the adenomas, 111In-octreotide showed a good sensibility in detecting GH-secreting tumors. In the second group, 111In-octeotride proved to be a good diagnostic tool to show carcinoid lesions which were missed by other complementary methodologies.