Exploring Environmental Chemicals and Risk of Breast Cancer During the Menopausal Transition

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1 Exploring Environmental Chemicals and Risk of Breast Cancer During the Menopausal Transition Susan L. Neuhausen, Ph.D Morris and Horowitz Families Endowed Professor Beckman Research Institute of City of Hope October 5, 2016

2 Disclosures I do not have anything to disclose

3 Breast cancer risk factors Age Environmental exposures Pregnancies Close Relative Menarche Menopause Hormones Weight Sex Genetics Exercise Known risk factors explain ~25%-50% of risk

4 Environmental chemicals/pollutants The U.S. EPA has registered approximately 85,000 synthetic chemicals for use. More than 200 chemicals have been shown in animal studies to increase mammary tumors. Timing of exposure is critical for some compounds BUT WE DO NOT KNOW The potential health effects of about 90% of the synthetic chemicals registered by U.S. EPA overall or at critical periods. The potential health effects of chronic, low-level human exposure to mixtures.

5 Exposures from physical environment Tobacco Smoke/Secondhand Smoke Personal Care Products Pharmaceuticals Radiation (medical and non-medical) Light-at-night Metals Combustion byproducts Hormones in food Solvents and industrial chemicals Pesticides Persistent organic pollutants (POPs) Flame retardants polybrominated diphenyl ethers (PBDEs) Plastics Bisphenol A (BPA)

6 Chemicals of concern - PBDEs Used primarily as flame retardants Class of over 200 brominated compounds Structurally similar to other carcinogenic organohalogenated compounds Introduced in the 1970s, they now represent one of the most pervasive environmental global contaminants Use particularly high in California: TB 117: has required since the 1980s that furniture sold in California pass a strict, 12-second flammability test

7 PBDEs: Exposures Readily leach out of products through normal use and disposal Exposures will continue for decades due to continued contact with and recycling of products in use e.g., 1 billion lbs. of recycled foam carpet cushioning is produced annually Other organohalogenated compounds are being introduced Limited data indicate the potential for carcinogenic and endocrine-disrupting effects Thyroid function Sex steroid hormonal pathways

8 Chemicals of concern: Bisphenol A (BPA) Virtually everyone has low levels of BPA in their body Primary exposure: canned foods and plastic beverage containers. Other exposures: dental fillings and sealants, CDs and DVDs, glass lenses, household electronics In animal studies, there is evidence of estrogenic effects of BPA, and of a link between low-level exposure and breast cancer 1945 Campbell s soup ad BUT WE DO NOT KNOW About the levels and impacts of human exposures and body burdens over time.

9 BPAs: Toxicology National Toxicology Program (NTP)

10 Institute of Medicine Report December 7, 2011

11 Life course approach Biology of breast development and origins and progression of breast cancer not fully understood Substantial changes in the breast through the life course, especially in response to hormonal signals Windows of susceptibility: timing of environmental exposures may be important Many agents never studied in ways relevant to breast cancer

12 Menopausal transition and window of susceptibility The time around menopause, also called the menopause transition Pre: regular menstrual periods Peri: irregular menstrual periods Post: no menstrual periods for more than 1 year Represents the permanent cessation of menses resulting from loss of ovarian follicular function, usually due to aging Widespread use of hormone replacement therapy for symptoms

13 Age-specific breast cancer incidence Age-specific incidence curves (log-log plots) for overall invasive and ductal carcinoma in situ from SEER data (From C Benz, Crit Rev Oncol Hematol, 2008, 66:65)

14 Incidence of invasive breast cancer in the Women s Health Initiative clinical trial E+P Placebo Cox regression models stratified by 5-year age-intervals. All women stopped intervention by 8.6 years. Duration of follow-up indicated by the dotted lines (From Chlebowski et al, JAMA, 2010; Original report JAMA, Vol288, 2002)

15 Decrease in U.S. breast cancer incidence after WHI study results published Ravdin et al., NEJM, 2007

16 Modeling the growth kinetics of breast tumors Incidence of total breast tumors expressed as a percentage of the population that reached the detection threshold over a period of 8 years compared with the incidence of de novo and occult tumors based on the OTG model (Santen; CEBP: 2012)

17 Hormone replacement therapy promotes the development of occult breast cancer Effect of hormone therapy on time to develop detectable breast tumors Incidence of breast tumors predicted in the placebo and hormone arms by Santen occult tumor growth (OTG) model (2013; Hormone Cancer)

18 Our BCERP study Hypothesis : During the menopausal transition, when natural hormone levels are actively declining, BPAs and PBDEs, acting as endocrine-disrupting chemicals, promote the development of hormone-responsive breast cancers. They may act individually or have additive or synergistic effects. S. Chen and S. Neuhausen NIHU01ES BCERP

19 Evidence-based complex-systems model of post-menopausal breast cancer Challenge to conduct population-based assessments of environmental factors From: RA Hiatt et al., CEBP, 2014 PMID:

20 Challenges in studying breast cancer and the environment Teasing out the biologic mechanisms of EDCs in epidemiologic studies is complicated Demonstrated effects of exposures in vitro assays and in vivo animal studies may not reflect what happens in human populations Therefore, we are using a multi-faceted, transdisciplinary approach to study potentially important mechanistic pathways in vitro cell line assays in vivo mouse models a population-based human study S. Chen and S. Neuhausen NIHU01ES BCERP

21 in vitro breast cell line assays Aro-ER tri-screen ERα and ERβ activity Progesterone activity Aromatase activity Aromatase promoter activity Cell proliferation

22 in vivo mouse models Test in OVX and VCD mice whether individual and combined effects cause mammary gland lesions during the menopausal transition

23 Population-based aim using the California Teachers Study Women ages years with menopausal status recorded at time of blood draw Composition of the study samples: 150 invasive breast cancers 97 in situ breast cancers 416 controls (114 pre-; 68 peri-; 234 post-menopausal) Assess the effects of BPA and PBDE levels in serum of women during the menopausal transition on: a) Total estrogenic activity, after accounting for endogenous levels b) Epigenomic changes: mirna global and gene-specific methylation c) Risk of breast cancer

24 PBDE congener concentrations

25 Differential gene methylation and levels of PBDE congeners Differential methylation in promoter regions ( Δβ > 0.2, FDR < 0.25) Congener Positive correlation Negative correlation BDE47 13 DMRs* 15 DMR BDE DMR 13 DMR BDE DMR 29 DMR *DMR = differentially methylated region

26 Differentially methylated regions in promoters of 42 genes associated with BDE153 levels

27 IPA of endocrine system development with DMR genes associated with BDE153 levels

28 Firefly/Renilla Ratio PR Reporter Assay: PBDE + R5020 treatment 1.2 PR Reporter Assay PR Reporter Neg control 0.2 0

29 Differentially expressed mirnas and levels of PBDE congeners Differentially expressed mirnas ( FC > 1.5, FDR < 0.25) Congener Positive correlation Negative correlation BDE47 1 mirna 0 mirna BDE mirna 5 mirna BDE153 2 mirna 0 mirna

30 Differentially expressed mirnas associated with BDE100 levels

31 Associations of two serum mirnas and BDE100 levels (10-73 ng/g) (6-8 ng/g) ( ng/g)

32 Summary A transdisciplinary approach may allow us to assess whether potential EDCs at levels in women promote the development of breast cancers at the menopausal transition Epigenetic changes are associated with levels of three PBDE congeners More to come: completion of cell line assays; testing of mouse models; BPA results, larger sample size, and association of epigenetic changes with development of breast cancer in human samples

33 Community engagement Develop resources and materials for educating and engaging the community on the role of environmental exposures and risk of developing breast cancer Our community leadership council

34 Acknowledgments Beckman Research Institute of the City of Hope Dr. Shiuan Chen Ms. Michele Rakoff Dr. Leslie Bernstein Dr. Kimlin Ashing Dr. Yuan Chun Ding Dr. Noriko Kanaye Dr. Tim Synold Mr. Charles Warden Ms. Mayra Serrano Ms. Linda Steele Ms. Lauren Carter The Cancer Prevention Institute of California Dr. Peggy Reynolds Dr. David Nelson Ms. Susan Hurley Environmental Chemistry Lab, Public Health Institute of California Dr. June-Soo Park Dr. Myrto Petreas Funded by NIH U01ES (Chen/Neuhausen)

35 Thank you and questions City of Hope Resources Cutting-Edge Ideas Collaboration Passion Dedication to Patients Commitment to Training