Evaluating the effects of bisphenol A on breast cancer development 

Breast Cancer UK has awarded a grant of £99,272 to Professor Valerie Speirs and colleagues Professor Paul Fowler, Dr Felix Grassman, Ms Beatrix Elsberger and Mr Yazan Masannat, University of Aberdeen, to fund a PhD studentship which examines the effects of bisphenol A (BPA) on breast cancer development. The project is expected to begin in October 2022.

Background 

Hormones, especially oestrogen, can influence the development of breast cancer. Exposure to naturally occurring hormones is unavoidable. However, we can take steps to reduce exposure to synthetic chemicals which mimic oestrogen. One of these is bisphenol A (BPA), a chemical used to make many plastics and resins for nearly 60 years. BPA is present in lots of everyday products, foods and drinks at low concentrations. Scientists worry about BPA because it is linked with increased disease risks. BPA can interfere with hormone-sensitive organs, like the breast. While a single exposure to BPA is unlikely to result in the development of breast cancer, repeated and frequent exposure to low concentrations of this chemical could contribute to the development of breast cancer.  

Project details 

This project will build on information obtained during our current BCUK-funded work. We will discover if there are links between exposure to BPA and breast cancer development in women, using a range of approaches made possible by the team of experts we have assembled to tackle this problem. We will start with a thorough review of the scientific literature to identify possible ways that BPA acts on breast tissue. At the same time, we will “mine” the data in large cancer-related gene databanks. We will combine the information we harvest to design laboratory experiments that will confirm if BPA-sensitive genes contribute to breast cancer development. This will then help us discover if levels of these BPA-sensitive genes in a woman’s breast will affect whether she will suffer from more dangerous, aggressive, breast cancer. To join these findings together we will measure BPA in tissue samples donated by breast cancer patients. This will confirm if there is a relationship between BPA levels and breast cancer. This project will provide conclusive evidence surrounding the role of BPA in breast cancer. 

Biomonitoring and molecular toxicity profiling of bisphenol mixtures   

Breast Cancer UK is pleased to announce we have awarded a grant of £100,000 to Dr Michael Antoniou and colleagues Dr Robin Mesnage and Dr Ana Rodriguez-Mateos, King’s College London, to fund a PhD studentship which will undertake biomonitoring of UK residents to identify levels of bisphenols and evaluate the potential breast cancer initiating and growth promoting activity of bisphenol mixtures. The project is expected to begin March 2022.

Project details 

Chemical exposure that interferes within the body’s hormone systems has been linked to breast cancer. Large numbers of pollutants can have oestrogen hormone-like activities and can stimulate breast cancer cell growth. The aim of this proposal is to evaluate the breast cancer promoting activity of mixtures of oestrogenic pollutants known as bisphenols.   

Bisphenols are used in the manufacture of plastic bottles, resins and the plastic lining of cans, from which they leach into food and drink. Bisphenol A (BPA) is the prototypical member of this class of plastics components, which is now known to mimic the effects of oestrogen. Due to public concerns, industry has been replacing BPA with other bisphenol compounds to produce so called “BPA-free” products. However, our Breast Cancer UK sponsored work has revealed that bisphenols used as BPA replacements also possess oestrogen hormone-like activity with some being more potent than BPA, and which fuel breast cancer cell growth. However, the exact mechanisms by which bisphenol mixtures may stimulate the development and progression of breast cancer remain unknown. In addition, bisphenol mixtures to which the UK population is exposed daily is unknown.    

This project will further investigate the connection between bisphenol mixture exposure and breast cancer by undertaking two lines of research. First, we will analyse the urine of UK residents to identify which bisphenols people ingest. Second, we will evaluate the breast cancer-causing and promoting potential of realistic cocktails of bisphenols by assessing their ability to stimulate the growth of normal human mammary epithelial cells and alter these cells’ characteristics to a cancerous state.   

This study will identify potential risks arising from bisphenol ingestion that can potentially lead to, or promote growth of, breast cancer.  

Multifactorial impacts on early breast carcinogenesis – assessing the combined effects of preventable factors on breast cancer using a novel Organ-On-a-Chip platform.

Breast Cancer UK has awarded a grant of £43,360 to Dr Elisabete Silva and colleagues, Drs Ruth MacKay, Sibylle Ermler and Emmanouil Karteris, Brunel University London, to fund research that examines the role of EDCs and saturated fatty acids on early stages of breast cancer. The project began in February 2020 and will finish February 2022.

Background and details of the research 

Lifestyle factors and environmental contaminants, including endocrine disrupting chemicals (EDCs), play a role in breast cancer development but human studies linking EDCs to cancer are often inconclusive. This is mainly because EDCs are studied individually and at concentrations that don’t match our day to day exposure. We are exposed to a cocktail of chemicals, which in combination, may have enhanced harmful effects.

Several studies support a link between a high fat diet and breast cancer, although this link is still debated, as what lies behind this effect is unclear. A high fat diet may not on its own be a serious contributor to breast cancer but its effect may be enhanced by the presence of EDCs in our bodies. The current project aims to address this knowledge gap. It will investigate the impact of complex mixtures of EDCs and saturated fatty acids (as found in a high fat diet) on breast tissue development and growth and initiation of breast cancer.

Dr Silva’s research will use an innovative “Breast-on-Chip” methodology developed at Brunel University. Different breast cell types are grown together in 3D cell culture and are fed with a constant flow of media and nutrients. This system is designed to mimic the physical environment of breast tissue. The approach provides a more robust and representative alternative to current laboratory and animal-based methods.

The EDCs to be tested include bisphenol A (plastic component), PBDEs (flame retardants), parabens (preservatives), benzophenones (UV filters), DDT (pesticide), polychlorinated biphenyls (used in hydraulic fluids, now banned) and galaxolide (perfume). The three most common fatty acids (lauric, palmitic and steric acids) and EDCs will be tested at concentrations that have been measured previously in human breast tissue.

The research aims to understand the impact of combinations of chemical exposures and lifestyle factors on early stages of breast carcinogenesis. This will provide a framework for further public information and practical advice on ways to reduce exposure to factors that contribute to breast cancer risk.

Previous funding: This is Dr Silva’s second BCUK grant. Her previous work investigated effects of low-dose mixtures of EDCs on breast cancer initiation using 3D breast cell culture. She found that low concentrations of 4 EDCs (propylparaben, BPA, DDT and benzophenone-3) added to breast cells grown in 3D cell culture caused changes resembling early stage breast cancer. When EDC mixtures were used, changes were more significant. Her new project uses a more sophisticated 3D model to examine the effects of EDCs in combination with saturated fatty acids

Examining how endocrine disrupting agents may modulate activity of fibroblasts generated from breast tissue of high and low mammographic density

Breast Cancer UK in collaboration with Animal Free Research UK have awarded a grant of £90,000 to Professor Valerie Speirs, University of Aberdeen, to fund a PhD studentship, which was awarded to Ms Kerri Palmer. The research project began October 2018 and will finish October 2021.

Project details

Breast density or mammographic density refers to how breasts appear on a mammogram. Breasts are made up of glandular tissue and fat tissue, held together by connective tissue (which contains cells known as fibroblasts). High breast density means there is a greater amount of connective and glandular tissue, compared to fat tissue. Women are 4-5 times more likely to get breast cancer if they have high breast density compared to those with low breast density (1, 2).

Breast density is partly inherited but is also influenced by the environment (3). It increases in response to hormones such as oestrogen, although how this occurs at the cellular level is unclear. Environmental factors that increase breast density include diet, alcohol (4) and synthetic hormones (3) such as hormone replacement therapy. Currently, it is unknown whether endocrine disrupting chemicals which mimic oestrogen contribute to changes in breast density. It is also unclear why high breast density increases breast cancer risk however it is believed to be associated with the activity of fibroblasts, (5). These cells are known to respond to hormones, but details are not fully understood.

This project is investigating the effects of oestrogen mimics on fibroblasts generated from human breast tissue, using a novel 3D in vitro human mammary gland model. This model uses different breast cell types grown together and represents the human breast more closely than epithelial breast cells grown in standard (2D) cell culture or animal models. The research will examine the effects of four oestrogen mimics on human fibroblasts derived from breast tissue of different breast density, in order to understand how these might affect breast density and in turn drive breast cancer development. The oestrogen mimics that will be used include the plastics component bisphenol A, plant-derived compounds genistein and resveratrol and the anti-miscarriage pill, diethylstilboestrol, which is no longer in use. RNA sequencing will be conducted on selected fibroblasts to identify which genes are affected by exposure to oestrogen mimics. Molecular biology techniques will be used to switch off or “silence” these genes. These fibroblasts will be incorporated into 3D breast cell models to establish if this influences the development of pre-invasive breast cancer.

The long-term objectives of the study are to identify biochemical pathways which mediate breast density, which could be modified to reduce the risk of breast cancer, and ultimately, identify a strategy which will help prevent breast cancer.

The research aims to replace two animal models of breast cancer, which are used currently by scientists, by using fully humanised animal free models.

More details about breast density and Professor Speirs’ research project 

References

1. Boyd et al. (2011). Mammographic density and breast cancer risk: current understanding and future prospects. Breast Cancer Research 13(6): 223. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3326547/
2. Sherratt, M. J. et al (2016). Raised mammographic density: causative mechanisms and biological consequences. Breast Cancer Research 18: 45. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4855337/pdf/13058_2016_Article_701.pdf
3. Huo, C. W. et al. (2014). Mammographic density a review on the current understanding of its association with breast cancer. Breast Cancer Research and Treatment 144: 479–502. https://www.ncbi.nlm.nih.gov/pubmed/24615497
4. Voevodina, O. et al. (2013). Association of Mediterranean diet, dietary supplements and alcohol consumption with breast density among women in South Germany: a cross-sectional study. BMC Public Health 13: 203 https://www.ncbi.nlm.nih.gov/pubmed/23497280
5. Luo H. et al. (2015). Cancer-associated fibroblasts: a multifaceted driver of breast cancer progression. Cancer Letters 361(2):155-163. https://www.ncbi.nlm.nih.gov/pubmed/25700776