Breast cancer is the most common malignancy in United States women, accounting for >40,000 deaths each year. These breast tumors are comprised of phenotypically diverse populations of breast cancer cells. Using a model in which human breast cancer cells were grown in immunocompromised mice, we found that only a minority of breast cancer cells had the ability to form new tumors. We were able to distinguish the tumorigenic (tumor initiating) from the nontumorigenic cancer cells based on cell surface marker expression. We prospectively identified and isolated the tumorigenic cells as CD44+CD24−/lowLineage− in eight of nine patients. As few as 100 cells with this phenotype were able to form tumors in mice, whereas tens of thousands of cells with alternate phenotypes failed to form tumors. The tumorigenic subpopulation could be serially passaged: each time cells within this population generated new tumors containing additional CD44+CD24−/lowLineage− tumorigenic cells as well as the phenotypically diverse mixed populations of nontumorigenic cells present in the initial tumor. The ability to prospectively identify tumorigenic cancer cells will facilitate the elucidation of pathways that regulate their growth and survival. Furthermore, because these cells drive tumor development, strategies designed to target this population may lead to more effective therapies.

/pdf/prospective-identification-of-tumorigenic-breast-cancer-4c9u5upfc3.pdf

Prospective identification of tumorigenic breast cancer cells

At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

/pdf/free-radicals-in-the-physiological-control-of-cell-function-g3w3iyr0ph.pdf

Free Radicals in the Physiological Control of Cell Function

Living in an oxygenated environment has required the evolution of effective cellular strategies to detect and detoxify metabolites of molecular oxygen known as reactive oxygen species. Here we review evidence that the appropriate and inappropriate production of oxidants, together with the ability of organisms to respond to oxidative stress, is intricately connected to ageing and life span.

Oxidants, oxidative stress and the biology of ageing.

http://aiocm.org/member/Immunity,%20Inflammation,%20and%20Cancer.pdf

Immunity, Inflammation, and Cancer

The secretion of glucocorticoids (GCs) is a classic endocrine response to stress. Despite that, it remains controversial as to what purpose GCs serve at such times. One view, stretching back to the time of Hans Selye, posits that GCs help mediate the ongoing or pending stress response, either via basal levels of GCs permitting other facets of the stress response to emerge efficaciously, and/or by stress levels of GCs actively stimulating the stress response. In contrast, a revisionist viewpoint posits that GCs suppress the stress response, preventing it from being pathologically overactivated. In this review, we consider recent findings regarding GC action and, based on them, generate criteria for determining whether a particular GC action permits, stimulates, or suppresses an ongoing stressresponse or, as an additional category, is preparative for a subsequent stressor. We apply these GC actions to the realms of cardiovascular function, fluid volume and hemorrhage, immunity and inflammation, metabolism, neurobiology, and reproductive physiology. We find that GC actions fall into markedly different categories, depending on the physiological endpoint in question, with evidence for mediating effects in some cases, and suppressive or preparative in others. We then attempt to assimilate these heterogeneous GC actions into a physiological whole. (Endocrine Reviews 21: 55‐ 89, 2000)

/pdf/how-do-glucocorticoids-influence-stress-responses-4egr3fa2k0.pdf

How do glucocorticoids influence stress responses? Integrating permissive, suppressive, stimulatory, and preparative actions.

Nuclear receptors and the AP-1 transcription factors (homodimers and heterodimers of members of the Jun/Fos/ATF/families) mutually influence their activities, positively and negatively. Mutual negative interference is of practical importance as it can be exploited for therapy of human diseases. Since the discovery of cross-modulation, many reports, seemingly not always compatible, have appeared. Recent experimental evidence may help to develop a model for this interesting transcription factor interaction that satisfies most observations. Transactivation and transrepression (as one facet o f cross-modulation) are separable activities o f the nuclear receptors. The modulating property appears to be exerted by nuclear receptor monomers. These conclusions are supported by point mutations in the glucocorticoid receptor and by the specific inhibitory effects of ligand analogues on transactivation only. These pilot experiments make a search for ligands that enhance the cross-modulatory function without triggering transactivation very promising.

https://www.cell.com/trends/endocrinology-metabolism/pdf/1043-2760(94)90164-3.pdf

Mutual cross-modulation of steroid/retinoic acid receptor and AP-1 transcription factor activities: a novel property with practical implications.

Tumor metastasis formation: cell-surface proteins confer metastasis-promoting or -suppressing properties

Phage T7 discontinues host gene expression by translational and transcriptional control mechanisms. Translational control is exerted by the T7 translational-repressor. This protein inhibits the synthesis of β-galactosidase (EC 3.2.1.23) in vivo and in vitro and the synthesis of the T3 enzyme S-adenosylmethioninehydrolase (EC 3.3.1.-). The translational-repressor does not interfere with T7-specific enzyme synthesis. The T7 translational-repressor purifies with the initiation factors. The repressor interacts with the initiation of translation of host enzymes. The translational-repressor gene is close to the promotor for RNA polymerase of Escherichia coli.

Peter Herrlich

Papers

Mutual cross-modulation of steroid/retinoic acid receptor and AP-1 transcription factor activities: a novel property with practical implications.

Tumor metastasis formation: cell-surface proteins confer metastasis-promoting or -suppressing properties

Translational Control Induced by Bacteriophage T7

Transcriptional and post-transcriptional responses to DNA-damaging agents.

CD44 variant–specific antibodies trigger hemopoiesis by selective release of cytokines from bone marrow macrophages