Hormonal control of p53 and chemoprevention

Improvements in the detection and treatment of breast cancer have dramatically altered its clinical course and outcome. However, prevention of breast cancer remains an elusive goal. Parity, age of menarche, and age at menopause are major risk factors drawing attention to the important role of the endocrine system in determining the risk of breast cancer, while heritable breast cancer susceptibility syndromes have implicated tumor suppressor genes as important targets. Recent work demonstrating hormonal modulation of the p53 tumor suppressor pathway draws together these established determinants of risk to provide a model of developmental susceptibility to breast cancer. In this model, the mammary epithelium is rendered susceptible due to impaired p53 activity during specific periods of mammary gland development, but specific endocrine stimuli serve to activate p53 function and to mitigate this risk. The results focus attention on p53 as a molecular target for therapies to reduce the risk of breast cancer

BDI logics for BDI architectures: old problems, new perspectives

International audienceThe mental attitudes of belief, desire, and intention play a central role in the design and implementation of autonomous agents. In 1987 Bratman proposed their integration into a belief-desire-intention (BDI) theory that was seminal in AI. Since then numerous approaches were built on the BDI paradigm, both practical (BDI architectures and BDI agents) and formal (BDI logics). The logical approaches that were most influential are due to Cohen&Levesque and to Rao&Georgeff. However, three fundamental problems remain up to now. First, the practical and the formal approaches evolved separately and neither fertilized the other. Second, only few formal approaches addressed some important issues such as the revision of intentions or the fundamentally paraconsistent nature of desires, and it seems fair to say that there is currently no consensual logical account of intentions. Finally, only few publications study the interaction between intention and other concepts that are naturally connected to intention, such as actions, planning, and the revision of beliefs and intentions. Our paper summarizes the state of the art, discusses the main open problems, and sketches how they can be addressed. We argue in particular that research on intention should be better connected to fields such as reasoning about actions, automated planning, and belief revision and update

Insulin, a key regulator of hormone responsive milk protein synthesis during lactogenesis in murine mammary explants

Murine milk protein gene expression requires insulin, hydrocortisone, and prolactin; however, the role of insulin is not well understood. This study, therefore, examined the requirement of insulin for milk protein synthesis. Mammary explants were cultured in various combinations of the lactogenic hormones and global changes in gene expression analysed using Affymetrix microarray. The expression of 164 genes was responsive to insulin, and 18 were involved in protein synthesis at the level of transcription and posttranscription, as well as amino acid uptake and metabolism. The folate receptor gene was increased by fivefold, highlighting a potentially important role for the hormone in folate metabolism, a process that is emerging to be central for protein synthesis. Interestingly, gene expression of two milk protein transcription factors, Stat5a and Elf5, previously identified as key components of prolactin signalling, both showed an essential requirement for insulin. Subsequent experiments in HCll cells confirmed that Stat5a and Elf5 gene expression could be induced in the absence of prolactin but in the presence of insulin. Whereas prolactin plays an essential role in phosphorylating and activating Stat5a, gene expression is only induced when insulin is present. This indicates insulin plays a crucial role in the transcription of the milk protein genes

Overview of mammary gland development: a comparison of mouse and human

The mouse mammary gland is widely used as a model for human breast cancer and has greatly added to our understanding of the molecular mechanisms involved in breast cancer development and progression. To fully appreciate the validity and limitations of the mouse model, it is essential to be aware of the similarities and also the differences that exist between the mouse mammary gland and the human breast. This introduction therefore describes the parallels and contrasts in mouse mammary gland and human breast morphogenesis from an early embryonic phase through to puberty, adulthood, pregnancy, parturition, and lactation, and finally the regressive stage of involution