Session 2: Windows of Susceptibility to Breast Carcinogenesis
Facilitator: Barbara Davis (NIEHS)
Discussion Questions:
What are the cellular targets in the mammary gland that could be affected by exposure to environmental agents during different developmental time periods?
What are the gaps in our knowledge with regard to understanding how chemicals/exposures impact the mammary gland during these periods?
Introduction
The second workshop session focused on windows of susceptibility to breast cancer. In introducing this topic, Barbara Davis emphasized that breast cancer is a complex disease that needs to be understood in the context of women's overall health. A woman's reproductive and endocrine status changes during her life span and it can influence susceptibility to breast cancer. Susceptibility is a complex function of exposure, age, hormonal milieu and other biosystem variants (i.e., diet, lifestyle, immune status). The role of environmental exposure should be understood in the context of many other factors that influence overall health and breast cancer susceptibility.
The term "breast cancer" refers to several different diseases that are differentiated by age of onset and hormone-dependence (i.e., early onset, late onset, estrogen-positive, estrogen-negative). The mammary gland undergoes several developmental changes during puberty, childbearing and menopause which may influence its susceptibility to breast cancer significantly. The breast also may contain cell populations that are more or less susceptible to exogenous or endogenous carcinogenic influences. Carcinogenic agents might influence the microenvironment of the breast or the macroenvironment of the breast (i.e., hormonal milieu, immune status).
Several studies indicate that chemical exposures may have long term or latent effects on breast cancer risk. For example, exposure in utero to PBBs has been correlated with precocious puberty. However, it is not yet known if in utero PBB-exposed females are at risk for breast cancer, although early onset of menarche is a known risk factor for breast cancer. Exposure to pesticides such as methoxychlor may also have latent effects on women's health not limited to effects on the mammary gland. These issues present significant challenges to understanding and preventing breast cancer and to identifying human breast carcinogens. It may be particularly important to identify and characterize the windows of susceptibility to breast cancer for optimal progress in this research area.
Key Discussion Points:
Etiology of post-menopausal breast cancer risk
Risk of breast cancer increases in post-menopausal women, and two thirds of all breast cancer in the U.S. occurs in post-menopausal women. Richard Santen (University of Virginia) and others felt that the molecular basis of post-menopausal susceptibility to breast cancer warrants more research. Walter Willet (Harvard School of Public Health) expressed the opinion that post-menopausal breast cancer is caused primarily by estrogen and that breast cancer risk may be increased by obesity and/or dietary factors.
Etiology of pre-menopausal breast cancer risk
Risk of breast cancer is higher in girls who experience menarche at an early age. Walter Willet indicated that an overall faster longitudinal growth rate may also be associated with early age of menarche, and thus growth rate may be linked to breast cancer risk. Dietary factors, such as consumption of large amounts of milk, may support faster growth in young girls. The combination of these factors needs to be assessed for their role in development of pre-menopausal breast cancer.
Breast density as a marker of breast cancer risk
Breast density is poorly characterized, both histologically and biologically. Increased breast density is correlated with increased (> 7x) post-menopausal breast cancer risk, and might be useful as a marker of risk. More studies of breast density are warranted.
Role of environmental carcinogens in human breast cancer is unclear
There is little compelling evidence suggesting that environmental chemicals are causal agents in breast cancer. In addition, increased overall breast cancer incidence is poorly correlated with increased exposure to industrial chemicals in the US population. Nevertheless, specific chemical exposures have not been ruled out as contributing factors for breast cancer risk. The National Toxicology Program has identified several rodent mammary carcinogens, but information on human exposure and human breast carcinogens is seriously limited. One example is phtalate, which is found in many cosmetics. Additionally, the promotional capacity of various environmental exposures to produce a cellular change that leads to breast cancer is not known. It was suggested that effects recent exposures versus effects of early life exposures to chemicals be assessed and evaluated.
Nutrition
Several researchers stated that the role of the diet and nutrition in inducing or protecting against cancer formation is not clear. More focused basic and applied research is needed on the molecular basis of the role of nutrients in cancer formation. It was noted that milk has high levels of progesterone and IGF. The effect of ongoing exposure to high levels of these compounds is unclear.
Environment and population heterogeneity
The impact of environmental exposures on a body can vary between populations. Large, international studies should be considered to account for and assess global heterogeneity. Temporal, spatial, and global studies about trends/changes in risk factor and disease incidence also is needed.
Research Focus
Some participants suggested that a change in breast cancer research policy might be needed. For example, research as to the reasons for the shift in the decrease in the age of puberty and the exposures in populations of girls at risk as opposed to breast cancer risks. This shift in research would allow for translation of the research of mechanisms that occur during exposures at critical time points to windows of increased carcinogenesis susceptibility.
Exposures to specific chemicals
The effects of exposure to specific chemicals are unclear. Temporal issues related to disease risk, tissue level concentrations, and pharmacokinetic data are needed to further assess the risks associated with exposures to these chemicals.
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