Environmental Effects on Inflammation and Cancer Development

Institution: University of California, Los Angeles
Investigator(s): Donald Lamkin, Ph.D. -
Award Cycle: 2017 (Cycle 23) Grant #: 23UB-7320 Award: $796,604
Award Type: SRI Request for Proposal (RFP)
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle

Initial Award Abstract (2017)

Non-technical overview of the research topic and relevance to breast cancer: Many breast cancer risk factors, by themselves, are only modestly associated with an increased chance for developing breast cancer. However, women may be exposed to several of these risk factors in their lives, and this combination of factors may ultimately increase their risk to a level far greater than that from either factor by itself. Of the many factors that may contribute to development of breast cancer, we plan to examine the combined effect of a suspect environmental chemical and an environmental social stressor. Clinical and epidemiological studies have shown that stress-related psychological factors in breast cancer patients, such as lack of social support, can associate with accelerated development of the disease and may do so by increasing the body's inflammation response. Likewise, certain environmental chemicals are hypothesized to act as tumor promoters through their effects on the body's inflammation response. Although animal models have been utilized to examine the effects of these factors individually on adverse health outcomes, rarely have both factors been examined at the same time and never at the same time in relation to breast cancer development. Among the several environmental chemicals that are hypothesized to induce systemic low-grade inflammation and promote tumor development are bisphenol A (BPA), which is used in plastic food packaging, and polybrominated diphenyl ethers (PBDEs), which are flame retardant chemicals in textiles, foams, and plastics. Among the several laboratory stressors that researchers use to induce stress is social isolation, where the mouse is housed alone instead of in a group. Given that rodents are a social species that abide in groups, social isolation in female mice is seen as a form of stress that may be analogous to deprivation of social support in humans. Thus, we will examine the effect of each suspect environmental chemical, in combination with social isolation, on mammary gland inflammation and tumor development.

Research question(s) or central hypotheses: Our first hypothesis is that mice exposed to a suspect environmental chemical and social stress have higher levels of mammary gland inflammation and greater development of tumor than mice exposed to just one of these factors or no factor. Our 2nd hypothesis asserts that mice exposed for longer time periods have higher levels of inflammation and greater development of tumor. This is based on the notion that longer duration equates to a higher "dose" of these pro-tumor factors. Our 3rd hypothesis acknowledges the possibility that "young age" may represent a window of increased vulnerability. We assert that mice exposed at an earlier age (pre-puberty) have higher levels of inflammation and greater development of tumor than mice exposed at older ages (post-puberty, post-pregnancy).

General methodology: Standard mouse models of breast cancer promotion will be used. After laboratory mice are randomly assigned to one of the experiment's conditions, they will undergo exposure to an environmental chemical for 12 weeks (in group or isolated housing) before a relatively small number of breast cancer cells are injected into the mammary gland. Mice in each group will then be monitored for another 4 weeks so that effects of exposure and social isolation on tumor development can be determined. Mammary gland will then be collected from each mouse so that effects of exposure and isolation on inflammation can be analyzed.

Innovative elements: This study may contribute to a major paradigm shift in our understanding of how environmental chemicals affect breast cancer risk: they increase low-grade inflammation in the body--an idea that is relatively new to cancer biology. In addition to measuring tumor size with standard handheld calipers, we will also be able to assess the metastatic potential of tumors by using imaging technology during tumor development to see if the growing tumor inside the living mouse has metastasized to other organs. This study also uses a genomics approach, which entails collecting tens of thousands of data points on gene expression from each mouse in the project, which will be shared on a public repository for other researchers to analyze.

Advocacy involvement and relevance to the human issues associated with breast cancer: Dr. Sandra Finestone, Director of the Hope Wellness Center in Irvine, California, is serving as the advocate on this proposal. As both a breast cancer survivor and clinical psychologist, Dr. Finestone provides counseling and social support to hundreds of women with breast cancer. Given her professional knowledge of the kinds of human stress that may impact upon breast cancer development, Dr. Finestone will provide ongoing feedback on the methods by which we aim to generate analogous stress hormone responses in laboratory mice that can impact mammary cancer development. She will also disseminate our findings to the breast cancer community.

Progress Report 1 (2018)

Topic Overview: Research suggests that certain environmental chemicals, such as bisphenol A (BPA) and polybrominated diphenyl ethers (PBDEs), may act as tumor promoters through indirect effects on inflammatory mechanisms. Similarly, other research in the behavioral sciences has shown that psychosocial stress may also promote tumor growth through such effects on similar inflammatory mechanisms. Given these findings, the current project is examining the combined effect of a suspect environmental chemical and an environmental social stressor on inflammatory signaling and tumor development in mouse models of breast cancer.

Degree to which the stated project aims were successfully completed: We successfully completed all experiments for Aim 1 in the first year as planned. Specifically, mice were exposed to a suspect environmental chemical (BPA or a PBDE) and social isolation for a duration of 3 months before a small number of breast cancer cells were injected into the mammary fat pads of the mice. We then monitored the expansion of cancer cells into a larger tumor for an additional 4 weeks with imaging technology, while environmental chemical administration and housing type were maintained. At the conclusion of each experiment, we dissected mammary tissue and began molecular processing operations to test for differences in inflammatory signaling as a function of chemical exposure and social isolation. We also dissected adrenal glands to test for differences in gene expression that are indicative of differential stress reactivity. In this first round of experiments, neither BPA nor PBDE appeared to have a significant effect on tumor growth, and this was regardless of whether the mice were socially isolated. However, analysis of gene expression in the adrenal gland showed downregulation in socially isolated mice, suggesting that the social isolation condition in these experiments is impacting stress biology.

Barriers: Analysis of differential inflammatory signaling in the mammary tissue is still being conducted due to delays in data processing. However, we anticipate being able to complete this analysis as the next reporting period begins.

Summary or list of major accomplishments: We believe the exposure period in these first experiments is the longest amount of time that any controlled preclinical research experiment has utilized to examine effects of BPA or PBDEs. Given the purported concern about accumulation of PBDEs in fatty tissue (including mammary tissue), we also believe that a future report from this project about protracted accumulation of PBDE in a preclinical model would be the first of its kind.

Plans for continuation of the project topic: We have begun a collaboration with the Pasarow Mass Spectrometry Laboratory here at UCLA to begin determining levels of BPA and PBDE-47 in these mice so as to inform our dosing decisions in the next experiments. The next round of experiments will test effects of these environmental chemicals and social isolation in a different model as initially planned for Year 2 of the project.