Endocrine disrupting chemicals and breast cancer cells.

Many hundreds of endocrine disrupting chemicals (EDCs) have been measured as entering human breast tissue from a range of environmental sources, and this review focuses on discussion of mechanisms by which such EDCs may be contributing to the globally rising incidence of breast cancer. Many of the distinguishing features of breast cancer may be accounted for by EDC exposure, including, but not limited to, the fact that many EDCs possess estrogenic activity and exposure to estrogen is a main risk factor for breast cancer. Studies of the actions of EDCs in human breast cancer cells are aided by use of the conceptual framework of the hallmarks of cancer, and, acting by a variety of genomic and nongenomic mechanisms, EDCs have now been shown to enable all the hallmarks of cancer to develop in human breast cancer cells.

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

Extensive use of triclosan (2,4,4'-trichloro-2'-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.

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.

Low-dose environmental endocrine disruptors, increase aromatase activity, estradiol biosynthesis and cell proliferation in human breast cells.

Background: Phenolic endocrine-disrupting compounds (EDCs) have long been suspected of increasing human breast cancer risk, via aromatase up-regulation; however, the metabolic effects upon aromatase in human breast cells exposed to environmentally relevant concentrations of phenolic compounds, have not been addressed.

Objectives: To examine the mechanistic responses of aromatase CYP19A1 mRNA, aromatase activity, estradiol biosynthesis and cellular proliferation, in three human breast cell lines, exposed to seven phenolic compounds, at environmentally relevant concentrations.

Methods: MCF-7 and ZR-75-1 breast cancer cells, and HMF3A breast fibroblasts were treated with specific concentrations of p,p'-DDT, methoxychlor, benzophenone-2, bisphenol A, bisphenol S, 4-phenylphenol and n-butylparaben, with and without the presence of aromatase inhibitors and estrogen receptor inhibitors.

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 (EDCs). 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, alkylphenols, fragrance compounds, organobromine flame retardants, fluorosurfactants), industrial chemicals (polychlorinated biphenyls), products of combustion (polychlorinated dibenzodioxins/furans, polyaromatic hydrocarbons), pesticides, herbicides, and some metals.

Effects of exposure to six chemical ultraviolet filters commonly used in personal care products on motility of MCF-7 and MDA-MB-231 human breast cancer cells in vitro.

Benzophenone (BP)-1, BP-2, BP-3, octylmethoxycinnamate (OMC), 4-methylbenzilidenecamphor and homosalate are added to personal care products to absorb ultraviolet light. Their presence in human milk and their oestrogenic activity suggests a potential to influence breast cancer development. As metastatic tumour spread is the main cause of breast cancer mortality, we have investigated the effects of these compounds on migration and invasion of human breast cancer cell lines.

Endocrine Disruptors and Obesity.

Purpose Of Review: The purpose of this review was to summarise current evidence that some environmental chemicals may be able to interfere in the endocrine regulation of energy metabolism and adipose tissue structure.

Recent Findings: Recent findings demonstrate that such endocrine-disrupting chemicals, termed "obesogens", can promote adipogenesis and cause weight gain. This includes compounds to which the human population is exposed in daily life through their use in pesticides/herbicides, industrial and household products, plastics, detergents, flame retardants and as ingredients in personal care products.

Exposure to cyclic volatile methylsiloxanes (cVMS) causes anchorage-independent growth and reduction of BRCA1 in non-transformed human breast epithelial cells.

Dermal absorption of components of personal care products (PCPs) may contribute to breast cancer development. Cyclic volatile methylsiloxanes (cVMS) are used widely in the formulation of PCPs, and their presence has been recently detected in human blood. The objectives of this study were to investigate any genotoxic effects after short- (1 week) or longer-term (30 weeks) exposure to hexamethylcyclotrisiloxane (D3), octamethylcyclotetrasiloxane (D4) or decamethylcyclopentasiloxane (D5) in MCF-10 A and MCF-10F immortalized non-transformed human breast epithelial cells.

Effect of aluminium on migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells in culture.

Aluminium (Al) has been measured in human breast tissue, and may be a contributory factor in breast cancer development. At the 10th Keele meeting, we reported that long-term exposure to Al could increase migratory properties of oestrogen-responsive MCF-7 human breast cancer cells suggesting a role for Al in the metastatic process. We now report that long-term exposure (20-25 weeks) to Al chloride or Al chlorohydrate at 10(-4) M or 10(-5) M concentrations can also increase the migration of oestrogen unresponsive MDA-MB-231 human breast cancer cells as measured using time-lapse microscopy and xCELLigence technology.

Parabens can enable hallmarks and characteristics of cancer in human breast epithelial cells: a review of the literature with reference to new exposure data and regulatory status.

A framework for understanding the complexity of cancer development was established by Hanahan and Weinberg in their definition of the hallmarks of cancer. In this review, we consider the evidence that parabens can enable development in human breast epithelial cells of four of six of the basic hallmarks, one of two of the emerging hallmarks and one of two of the enabling characteristics. In Hallmark 1, parabens have been measured as present in 99% of human breast tissue samples, possess oestrogenic activity and can stimulate sustained proliferation of human breast cancer cells at concentrations measurable in the breast.

Exposure to parabens at the concentration of maximal proliferative response increases migratory and invasive activity of human breast cancer cells in vitro.

Alkyl esters of p-hydroxybenzoic acid (parabens) are widely used as preservatives in personal care products, foods and pharmaceuticals. Their oestrogenic activity, their measurement in human breast tissue and their ability to drive proliferation of oestrogen-responsive human breast cancer cells has opened a debate on their potential to influence breast cancer development. As proliferation is not the only hallmark of cancer cells, we have investigated the effects of exposure to parabens at concentrations of maximal proliferative response on migratory and invasive properties using three oestrogen-responsive human breast cancer cell lines (MCF-7, T-47-D, ZR-75-1).

Hypersensitivity and growth adaptation of oestrogen-deprived MCF-7 human breast cancer cells.

Background: Efficacy of endocrine therapy is compromised when human breast cancer cells circumvent imposed growth inhibition. The model of long-term oestrogen-deprived MCF-7 human breast cancer cells has suggested the mechanism results from hypersensitivity to low levels of residual oestrogen.

Materials And Methods: MCF-7 cells were maintained for up to 30 weeks in phenol-red-free medium and charcoal-stripped serum with 10(-8) M 17β-oestradiol and 10 μg/ml insulin (stock 1), 10(-8) M 17β-oestradiol (stock 2), 10 μg/ml insulin (stock 3) or no addition (stock 4).

Aluminium and breast cancer: Sources of exposure, tissue measurements and mechanisms of toxicological actions on breast biology.

This review examines recent evidence linking exposure to aluminium with the aetiology of breast cancer. The human population is exposed to aluminium throughout daily life including through diet, application of antiperspirants, use of antacids and vaccination. Aluminium has now been measured in a range of human breast structures at higher levels than in blood serum and experimental evidence suggests that the tissue concentrations measured have the potential to adversely influence breast epithelial cells including generation of genomic instability, induction of anchorage-independent proliferation and interference in oestrogen action.

Effect of aluminium on migratory and invasive properties of MCF-7 human breast cancer cells in culture.

Aluminium (Al) has been measured in human breast tissue, nipple aspirate fluid and breast cyst fluid, and recent studies have shown that at tissue concentrations, aluminium can induce DNA damage and suspension growth in human breast epithelial cells. This paper demonstrates for the first time that exposure to aluminium can also increase migratory and invasive properties of MCF-7 human breast cancer cells. Long-term (32 weeks) but not short-term (1 week) exposure of MCF-7 cells to 10(-4) M aluminium chloride or 10(-4) M aluminium chlorohydrate increased motility of the cells as measured by live cell imaging (cumulative length moved by individual cells), by a wound healing assay and by migration in real time through 8 μm pores of a membrane using xCELLigence technology.

Combinations of parabens at concentrations measured in human breast tissue can increase proliferation of MCF-7 human breast cancer cells.

The alkyl esters of p-hydroxybenzoic acid (parabens), which are used as preservatives in consumer products, possess oestrogenic activity and have been measured in human breast tissue. This has raised concerns for a potential involvement in the development of human breast cancer. In this paper, we have investigated the extent to which proliferation of MCF-7 human breast cancer cells can be increased by exposure to the five parabens either alone or in combination at concentrations as recently measured in 160 human breast tissue samples.

Parabens enable suspension growth of MCF-10A immortalized, non-transformed human breast epithelial cells.

Parabens (alkyl esters of p-hydroxybenzoic acid) are used extensively as preservatives in consumer products, and intact esters have been measured in several human tissues. Concerns of a potential link between parabens and breast cancer have been raised, but mechanistic studies have centred on their oestrogenic activity and little attention has been paid to any carcinogenic properties. In the present study, we report that parabens can induce anchorage-independent growth of MCF-10A immortalized but non-transformed human breast epithelial cells, a property closely related to transformation and a predictor of tumour growth in vivo.

Molecular mechanisms of oestrogen action on growth of human breast cancer cells in culture.

Growth responses to oestrogen can be reproducibly obtained using a selection of oestrogen-receptor-containing human breast cancer cell lines, and molecular mechanisms have been shown to include modulation to growth factor/receptor/signalling pathways, cell-cycle proteins, apoptosis, differentiation, adhesion, motility and migration. Considerable progress has been made in understanding the molecular basis of oestrogen action on gene expression through the ligand-activated transcription factors human oestrogen receptor α (ERα) and ERβ and the resulting effects on global gene expression patterns, but the full profile of coordination of the alterations, which brings about changes in cell growth through genomic and non-genomic mechanisms remain to be fully elucidated. Oestrogen regulation of cell growth involves a complex cross-talk between oestrogen receptor and growth factor signalling pathways such that inhibition of one pathway may lead to stimulation of another, which may explain the remarkable ability of human breast cancer cells to escape from any mode of imposed growth inhibition be it oestrogen deprivation or administration of antioestrogen.

Crosstalk with insulin and dependence on PI3K/Akt/mTOR rather than MAPK pathways in upregulation of basal growth following long-term oestrogen deprivation in three human breast cancer cell lines.

Background: MCF-7, T-47-D, ZR-75-1 human breast cancer cell lines are dependent on oestrogen for growth but can adapt to grow during long-term oestrogen deprivation. This serves as a model for identification of therapeutic targets in endocrine-resistant breast cancer.

Methods: An overlooked complication of this model is that it involves more than non-addition of oestrogen, and inadequate attention has been given to separating molecular events associated with each of the culture manipulations.

Analysis of aluminium content and iron homeostasis in nipple aspirate fluids from healthy women and breast cancer-affected patients.

Aluminium is not a physiological component of the breast but has been measured recently in human breast tissues and breast cyst fluids at levels above those found in blood serum or milk. Since the presence of aluminium can lead to iron dyshomeostasis, levels of aluminium and iron-binding proteins (ferritin, transferrin) were measured in nipple aspirate fluid (NAF), a fluid present in the breast duct tree and mirroring the breast microenvironment. NAFs were collected noninvasively from healthy women (NoCancer; n = 16) and breast cancer-affected women (Cancer; n = 19), and compared with levels in serum (n = 15) and milk (n = 45) from healthy subjects.

Enhanced sensitivity to rapamycin following long-term oestrogen deprivation in MCF-7, T-47-D and ZR-75-1 human breast cancer cells.

Human breast cancer cells (MCF-7, T-47-D and ZR-75-1) can adapt to circumvent any reduced growth rate during long-term oestrogen deprivation, and this provides three model systems to investigate mechanisms of endocrine resistance in breast cancer. In this paper we report consistent differences in the effects of three growth inhibitors following long-term oestrogen deprivation in all three cell models. Long-term oestrogen deprivation of MCF-7, T-47-D and ZR-75-1 cells resulted in reduced growth inhibition by PD98059 (2-10 μg/ml), implying a loss of dependence on mitogen-activated protein kinase pathways for growth.

Environmental oestrogens and breast cancer: evidence for combined involvement of dietary, household and cosmetic xenoestrogens.

Unlabelled: Many environmental compounds with oestrogenic activity are measurable in the human breast and oestrogen is a known factor in breast cancer development. Exposure to environmental oestrogens occurs through diet, household products and cosmetics, but concentrations of single compounds in breast tissue are generally lower than needed for assayable oestrogenic responses. Results presented here and elsewhere demonstrate that in combination, chemicals can give oestrogenic responses at lower concentrations, which suggests that in the breast, low doses of many compounds could sum to give a significant oestrogenic stimulus.

Differential effects of overexpression of ERα and ERβ in MCF10A immortalised, non-transformed human breast epithelial cells.

Background: Cellular effects of oestrogen are mediated by two intracellular receptors ERα and ERβ. However, to compare responses mediated through these two receptors, experimental models are needed where ERα and ERβ are individually stably overexpressed in the same cell type.

Methods: We compared the effects of stable overexpression of ERα and ERβ in the MCF10A cell line, which is an immortalised but non-transformed breast epithelial cell line without high endogenous ER expression.

Concentration of aluminium in breast cyst fluids collected from women affected by gross cystic breast disease.

Gross cystic breast disease (GCBD) is the most common benign breast disorder, but the molecular basis of cyst formation remains to be identified. If the use of aluminium-based antiperspirant salts is involved in the etiology of gross breast cyst formation, it might be expected that aluminium would be at elevated levels in human breast cyst fluid (BCF). Aluminium was measured by ICP-MS in 48 samples of BCF, 30 samples of human blood serum and 45 samples of human breast milk at different stages of lactation (colostrum, intermediate, mature).