Breast cysts and aluminium-based antiperspirant salts

On the basis that aluminium-based antiperspirant salts are designed to block apocrine sweat ducts of the axilla, and that breast cysts result from blocked breast ducts in the adjacent region of the body, it has been proposed that breast cysts may arise from antiperspirant use if sufficient aluminium is absorbed into breast tissues over long-term usage. This review collates evidence that aluminium can be absorbed from dermal application of antiperspirant salts and describes studies measuring levels of aluminium in breast tissues, including in breast cyst fluids. It is notable that breast cysts, as for breast cancers, start most frequently in the upper outer quadrant of the breast, which is the region closest to the site of underarm antiperspirant application. Mechanistic evidence is reviewed for a link between aluminium levels in breast tissue, cyst formation and development of breast cancer. If excessive use of antiperspirant is a cause of breast cysts, then reduction or cessation of use could provide a preventative or even treatment strategy. Furthermore, if cyst formation from antiperspirant use is an indicator of increased risk for breast cancer, then reduction in use of antiperspirant could also provide a strategy for reducing breast cancer risk

Overview of air pollution and endocrine disorders

Over recent years, many environmental pollutant chemicals have been shown to possess the ability to interfere in the functioning of the endocrine system and have been termed endocrine disrupting chemicals. These compounds exist in air as volatile or semi-volatile compounds in the gas phase or attached to particulate matter. They include components of plastics (phthalates, bisphenol A), components of consumer goods (parabens, triclosan, alkyl phenols, fragrance compounds, organobromine flame retardants, fluorosurfactants), industrial chemicals (polychlorinated biphenyls), products of combustion (polychlorinated dibenzodioxins/ furans, polyaromatic hydrocarbons), pesticides, herbicides and some metals. This review summarises current knowledge concerning the sources of endocrine disrupting chemicals in air, measurements of levels of endocrine disrupting chemicals in air and the potential for adverse effects of endocrine disrupting chemicals in air on human endocrine health

The potential for estrogen disrupting chemicals to contribute to migration, invasion and metastasis of human breast cancer cells

Estrogen disrupting chemicals are environmental compounds which mimic, antagonize or interfere in the action of physiological estrogens. They occur naturally (plant phytoestrogens) but the majority are man-made compounds, which, through their use in agricultural, industrial and consumer products, have become widely present in human tissues including breast tissue. Since exposure to estrogen is a risk factor for breast cancer, estrogen disrupting chemicals may also contribute to breast cancer development. This review discusses evidence implicating estrogen disrupting chemicals in increasing migratory and invasive activity of breast epithelial cells, in epithelial-to-mesenchymal transition, and in growth of breast tumours at metastatic sites as well as the primary site. Mechanisms may be through the ability of such chemicals to bind to estrogen receptors, but unlike for proliferation, effects on cell migration and invasion are not limited to estrogen receptor-mediated mechanisms. Furthermore, whilst effects on proliferation can be measured within hours/days of adding an estrogen disrupting chemical to estrogen-responsive breast cancer cells, effects on cell migration occur after longer times (weeks). Most studies have focused on individual chemicals, but there is now a need to consider the environmentally relevant effects of long-term, low-dose exposure to complex mixtures of estrogen disrupting chemicals on mechanisms of metastasis

Chemical components of plastics as endocrine disruptors: overview and commentary

Bisphenol A and phthalate esters are used as additives in the manufacture of plastic materials, but their ability to leach out with age and heat has resulted in their becoming ubiquitous contaminants of the ecosystem including within human body tissues. Over recent years, these compounds have been shown to possess endocrine disrupting properties with an ability to interfere in the actions of many hormones and to contribute to human health problems. Much of the reported disruptive activity has been in relation to the action of estrogens, androgens, and thyroid hormones, and concerns have been raised for adverse consequences on female and male reproductive health, thyroid function, metabolic alterations, brain development/function, immune responses, and development of cancers in hormone-sensitive tissues. A recurring theme throughout seems to be that there are windows of susceptibility to exposure in utero and in early postnatal life, which may then result in disease in later life without any need for further exposure. This commentary highlights key issues in a historical context and raises questions regarding the many data gaps

Peptide dendrimer/lipid hybrid systems are efficient DNA transfection reagents: structure--activity relationships highlight the role of charge distribution across dendrimer generations.

Efficient DNA delivery into cells is the prerequisite of the genetic manipulation of organisms in molecular and cellular biology as well as, ultimately, in nonviral gene therapy. Current reagents, however, are relatively inefficient, and structure-activity relationships to guide their improvement are hard to come by. We now explore peptide dendrimers as a new type of transfection reagent and provide a quantitative framework for their evaluation. A collection of dendrimers with cationic and hydrophobic amino acid motifs (such as KK, KA, KH, KL, and LL) distributed across three dendrimer generations was synthesized by a solid-phase protocol that provides ready access to dendrimers in milligram quantities. In conjunction with a lipid component (DOTMA/DOPE), the best reagent, G1,2,3-KL ((LysLeu)8(LysLysLeu)4(LysLysLeu)2LysGlySerCys-NH2), improves transfection by 6-10-fold over commercial reagents under their respective optimal conditions. Emerging structure-activity relationships show that dendrimers with cationic and hydrophobic residues distributed in each generation are transfecting most efficiently. The trigenerational dendritic structure has an advantage over a linear analogue worth up to an order of magnitude. The success of placing the decisive cationic charge patterns in inner shells rather than previously on the surface of macromolecules suggests that this class of dendrimers significantly differs from existing transfection reagents. In the future, this platform may be tuned further and coupled to cell-targeting moieties to enhance transfection and cell specificity

Long-term exposure to triclosan increases migration and invasion of human breast epithelial cells in vitro

Extensive use of triclosan (2,4,40-trichloro-20-hydroxydiphenyl ether) as an antimicrobial agent in household and personal care products has resulted in global exposure of the human population. Its presence in human tissues, including milk, and its oestrogen-disrupting properties raise concerns for an involvement in breast cancer. Because metastatic tumour spread is the main cause of breast cancer mortality, we have investigated the effects of triclosan on cell migration and invasion using three human breast epithelial cell lines and using concentrations comparable with those in human tissues. Long-term exposure to 10−7 M of triclosan resulted in increased migration and invasion as measured by xCELLigence technology for all three cell lines, for the immortalized but nontransformed MCF-10F breast epithelial cells (after 28 weeks), the oestrogen-responsive MCF-7 breast cancer cells (after 17 weeks) and the oestrogen-unresponsive MDA-MB-231 breast cancer cells (after 20 weeks). The effects were therefore not limited to cancerous cells or to oestrogen-responsive cells. This was paralleled in the MCF-10F and MCF-7 (but not MDA-MB-231) cells by a reduction in levels of E-cadherin mRNA as measured by reverse transcription–polymerase chain reaction (RT-PCR) and of E-cadherin protein as measured by western immunoblotting, suggesting a mechanism involving epithelialto-mesenchymal transition. This adds triclosan to the increasing list of ingredients of personal care products that can not only enter human breast tissue and increase cell proliferation but also influence cell motility. If mixtures of components in household and personal care products contribute to increasing cell migration and invasion, then reduction in exposure could offer a strategy for reducing breast cancer spread

Replicating viral vector platform exploits alarmin signals for potent CD8+ T cell-mediated tumour immunotherapy

Viral infections lead to alarmin release and elicit potent cytotoxic effector T lymphocyte (CTLeff) responses. Conversely, the induction of protective tumour-specific CTLeff and their recruitment into the tumour remain challenging tasks. Here we show that lymphocytic choriomeningitis virus (LCMV) can be engineered to serve as a replication competent, stably-attenuated immunotherapy vector (artLCMV). artLCMV delivers tumour-associated antigens to dendritic cells for efficient CTL priming. Unlike replication-deficient vectors, artLCMV targets also lymphoid tissue stroma cells expressing the alarmin interleukin-33. By triggering interleukin-33 signals, artLCMV elicits CTLeff responses of higher magnitude and functionality than those induced by replication-deficient vectors. Superior anti-tumour efficacy of artLCMV immunotherapy depends on interleukin-33 signalling, and a massive CTLeff influx triggers an inflammatory conversion of the tumour microenvironment. Our observations suggest that replicating viral delivery systems can release alarmins for improved anti-tumour efficacy. These mechanistic insights may outweigh safety concerns around replicating viral vectors in cancer immunotherapy