Are Trp53 rescue of Brca1 embryonic lethality and Trp53/Brca1 breast cancer association related?

Brca1 is involved in multiple biological pathways including DNA damage repair, transcriptional regulation, and cell-cycle progression. A complex pattern of interactions of Brca1 with Trp53 has also emerged. Xu and coworkers found that haploid loss of Trp53 significantly reduces the embryonic lethality observed in mice with a homozygous in-frame deletion of Brca1 exon 11. They report that widespread apoptosis correlates with the embryonic lethality resulting from this homozygous Δ11 Brca1 mutation. A mechanism responsible for Brca1-associated carcinogenesis is proposed. These experiments extend our knowledge of a complex Brca1/Trp53 relationship. However, the precise mechanisms through which Brca1 interacts with Trp53 to suppress mammary tumor formation have yet to be elucidated

Conditional Inactivation of Brca1, p53 and Rb in Mouse Ovaries Results in the Development of Leiomyosarcomas

Epithelial ovarian cancer (EOC) is thought to arise in part from the ovarian surface epithelium (OSE); however, the molecular events underlying this transformation are poorly understood. Germline mutations in the BRCA1 tumor suppressor gene result in a significantly increased risk of developing EOC and a large proportion of sporadic EOCs display some sort of BRCA1 dysfunction. To generate a model in which Brca1-mediated transformation can be studied, we previously inactivated Brca1 alone in murine OSE, which resulted in an increased accumulation of premalignant changes, but no tumor formation. In this study, we examined tumor formation in mice with conditionally expressed alleles of Brca1, p53 and Rb, alone or in combination. Intrabursal injection of adenovirus expressing Cre recombinase to inactivate p53 resulted in tumors in 100% of mice. Tumor progression was accelerated in mice with concomitant inactivation of Brca1 and p53, but not Rb and p53. Immunohistologic analyses classified the tumors as leiomyosarcomas that may be arising from the ovarian bursa. Brca1 inactivation in primary cultures of murine OSE cells led to a suppression of proliferation that could be rescued by concomitant inactivation of p53 and/or Rb. Brca1-deficient OSE cells displayed an increased sensitivity to the DNA damaging agent cisplatin, and this effect could be modulated by inactivation of p53 and/or Rb. These results indicate that Brca1 deficiency can accelerate tumor development and alter the sensitivity of OSE cells to chemotherapeutic agents. Intrabursal delivery of adenovirus intended to alter gene expression in the ovarian surface epithelium may, in some strains of mice, result in more rapid transformation of adjacent cells, resulting in leiomyosarcomas

Characterization of NLRP12 during the Development of Allergic Airway Disease in Mice

Among the 22 members of the nucleotide binding-domain, leucine rich repeat-containing (NLR) family, less than half have been functionally characterized. Of those that have been well studied, most form caspase-1 activating inflammasomes. NLRP12 is a unique NLR that has been shown to attenuate inflammatory pathways in biochemical assays and mediate the lymph node homing of activated skin dendritic cells in contact hypersensitivity responses. Since the mechanism between these two important observations remains elusive, we further evaluated the contribution of NLRP12 to organ specific adaptive immune responses by focusing on the lung, which, like skin, is exposed to both exogenous and endogenous inflammatory agents. In models of allergic airway inflammation induced by either acute ovalbumin (OVA) exposure or chronic house dust mite (HDM) antigen exposure, Nlrp12−/− mice displayed subtle differences in eosinophil and monocyte infiltration into the airways. However, the overall development of allergic airway disease and airway function was not significantly altered by NLRP12 deficiency. Together, the combined data suggest that NLRP12 does not play a vital role in regulating Th2 driven airway inflammation using common model systems that are physiologically relevant to human disease. Thus, the allergic airway inflammation models described here should be appropriate for subsequent studies that seek to decipher the contribution of NLRP12 in mediating the host response to agents associated with asthma exacerbation

Long-term (trophic) purinergic signalling: purinoceptors control cell proliferation, differentiation and death

The purinergic signalling system, which uses purines and pyrimidines as chemical transmitters, and purinoceptors as effectors, is deeply rooted in evolution and development and is a pivotal factor in cell communication. The ATP and its derivatives function as a 'danger signal' in the most primitive forms of life. Purinoceptors are extraordinarily widely distributed in all cell types and tissues and they are involved in the regulation of an even more extraordinary number of biological processes. In addition to fast purinergic signalling in neurotransmission, neuromodulation and secretion, there is long-term (trophic) purinergic signalling involving cell proliferation, differentiation, motility and death in the development and regeneration of most systems of the body. In this article, we focus on the latter in the immune/defence system, in stratified epithelia in visceral organs and skin, embryological development, bone formation and resorption, as well as in cancer. Cell Death and Disease (2010) 1, e9; doi:10.1038/cddis.2009.11; published online 14 January 201

Role of BRCA gene dysfunction in breast and ovarian cancer predisposition

Tumor suppressor genes that perform apparently generic cellular functions nonetheless cause tissue-specific syndromes in the human population when they are mutated in the germline. The two major hereditary breast/ovarian cancer predisposition genes, BRCA1 and BRCA2, appear to participate in a common pathway that is involved in the control of homologous recombination and in the maintenance of genomic integrity. How might such functions translate into the specific suppression of cancers of the breast and ovarian epithelia? Recent advances in the study of BRCA1 and BRCA2, discussed herein, have provided new opportunities to address this question

Knockout and transgenic mice of Trp53: what have we learned about p53 in breast cancer?

The human p53 tumor suppressor gene TP53 is mutated at a high frequency in sporadic breast cancer, and Li-Fraumeni syndrome patients who carry germline mutations in one TP53 allele have a high incidence of breast cancer. In the 10 years since the first knockout of the mouse p53 tumor suppressor gene (designated Trp53) was published, much has been learned about the contribution of p53 to biology and tumor suppression in the breast through the use of p53 transgenic and knockout mice. The original mice deficient in p53 showed no mammary gland phenotype. However, studies using BALB/c-Trp53-deficient mice have demonstrated a delayed involution phenotype and a mammary tumor phenotype. Together with other studies of mutant p53 transgenes and p53 bitransgenics, a greater understanding has been gained of the role of p53 in involution, of the regulation of p53 activity by hormones, of the effect of mouse strain and modifier genes on tumor phenotype, and of the cooperation between p53 and other oncogenic pathways, chemical carcinogens and hormonal stimulation in mammary tumorigenesis. Both p53 transgenic and knockout mice are important in vivo tools for understanding breast cancer, and are yet to be exploited for developing therapeutic strategies in breast cancer

Preclinical mouse models for BRCA1-associated breast cancer

A substantial part of all hereditary breast cancer cases is caused by BRCA1 germline mutations. In this review, we will discuss the insights into BRCA1 functions that we obtained from mouse models with conventional and conditional mutations in Brca1. The most advanced models closely resemble human BRCA1-related breast cancer and may therefore be useful for addressing clinically relevant questions

Shaping immune responses through the activation of dendritic cells–P2 receptors

Dendritic cells (DCs) activate and shape the adaptive immune response by capturing antigens, migrating to peripheral lymphoid organs where naïve T cells reside, expressing high levels of MHC and costimulatory molecules and secreting cytokines and chemokines. DCs are endowed with a high degree of functional plasticity and their functions are tightly regulated. Besides initiating adaptive immune responses, DCs play a key role in maintaining peripheral tolerance toward self-antigens. On the basis of the information gathered from the tissue where they reside, DCs adjust their functional activity to ensure that protective immunity is favoured while unwanted or exaggerated immune responses are prevented. A wide variety of signals from neighbouring cells affecting DC functional activity have been described. Here we will discuss the complex role of extracellular nucleotides in the regulation of DC function and the role of P2 receptors as possible tools to manipulate immune responses

Unlocking the power of cross-species genomic analyses: identification of evolutionarily conserved breast cancer networks and validation of preclinical models

The application of high-throughput genomic technologies has revealed that individual breast tumors display a variety of molecular features that require more personalized approaches to treatment. Several recent studies have demonstrated that a cross-species analytic approach provides a powerful means to filter through genetic complexity by identifying evolutionarily conserved genetic networks that are fundamental to the oncogenic process. Mouse-human tumor comparisons will provide insights into cellular origins of tumor subtypes, define interactive oncogenetic networks, identify potential novel therapeutic targets, and further validate as well as guide the selection of genetically engineered mouse models for preclinical testing