Diane M. Klotz

Synergistic Activation of Estrogen Receptor with Combinations of Environmental Chemicals

Certain chemicals in the environment are estrogenic. The low potencies of these compounds, when studied singly, suggest that they may have little effect on biological systems. The estrogenic potencies of combinations of such chemicals were screened in a simple yeast estrogen system (YES) containing human estrogen receptor (hER). Combinations of two weak environmental estrogens, such as dieldrin, endosulfan, or toxaphene, were 1000 times as potent in hER-mediated transactivation as any chemical alone. Hydroxylated polychlorinated biphenyls shown previously to synergistically alter sexual development in turtles also synergized in the YES. The synergistic interaction of chemical mixtures with the estrogen receptor may have profound environmental implications. These results may represent a previously uncharacterized level of regulation of estrogen-associated responses.

Inhibition of 17 beta-estradiol and progesterone activity in human breast and endometrial cancer cells by carbamate insecticides

Using a combination of in vitro assays we have examined the capacities of contemporary-exposure chemicals to modulate human estrogen and human progesterone receptor (hER and hPR) activity in human breast and endometrial cancer cells. The carbamate insecticides aldicarb, Baygon (propoxur), bendiocarb, carbaryl, methomyl, and oxamyl were used in this study. The carbamates alone weakly activated estrogen- or progesterone-responsive reporter genes in breast and endometrial cancer cells. All of the carbamates decreased estradiol- or progesterone-induced reporter gene activity in the breast and endometrial cancer cells. In whole cell competition binding assays, the carbamates demonstrated a limited capacity to displace radiolabeled estrogen or progesterone from ER or PR. Based on the results presented here, the carbamate insecticides may represent a class of chemicals which function through a mechanism separate from ligand-binding and, therefore, may act as general endocrine modulators in mammalian cells.

Differential responsiveness of MCF‐7 human breast cancer cell line stocks to the pineal hormone, melatonin

The estrogen receptor (ER)‐positive MCF‐7 human breast cancer cell line has been used extensively for the study of estrogen‐responsive human breast cancer. However, various levels of estrogen responsiveness have been described in different stocks of MCF‐7 cells. Because we have previously shown that the pineal hormone, melatonin, inhibits proliferation of MCF‐7 cells and can modulate ER expression and transactivation, we investigated if various stocks of MCF‐7 cells exhibit a differential responsiveness to the anti‐proliferative effects of melatonin and the possible mechanisms involved. The MCF‐7 stocks (M, O, H) were examined for: (1) mitogenic response to estradiol; (2) steady‐state ER mRNA levels; (3) expression of the mt1 melatonin membrane receptor; (4) growth inhibition by melatonin; and (5) melatonins modulation of expression of the ER and the estrogen‐regulated genes, PgR, TGFβ and pS2. For all of these parameters, there was a stock‐specific response which showed: MCF‐7M>MCF‐7O>MCF‐7 H. These results demonstrate that there are significant differences in the responsiveness of various stocks of MCF‐7 breast cancer cells to the growth‐inhibitory effects of melatonin which can be correlated with both the level of ER mRNA expression and the degree of estrogen‐responsiveness. These findings suggest that not only may these differences have some impact on the cells’ estrogen‐response pathway, but also that the primary growth‐inhibitory effects of melatonin are transduced through the membrane‐associated G‐protein coupled mt1 melatonin receptor.

Genetics of Breast Cancer

For women in the United States, the risk of developing breast cancer by age 85 years is currently about one in eight. It is clear that this disease arises from multiple causes, many of which can even occur within the same extended family. Etiological factors of breast cancer such as social class, body mass, and age at menarche appear to be interrelated, and to occur within certain families without necessarily having a genetic basis. In addition, even when the pattern of breast cancer in a given family strongly suggests that the trait for breast cancer susceptibility is inherited, the apparent mode of inheritance frequently does not conform to the principles of mendelian genetics. Determining the heritability of the trait within a family is often complicated by incomplete penetrance, i.e., by the presence of individuals who appear to have inherited susceptibility to breast cancer without developing the disease themselves. The presence of some individuals in which the cancer may have occurred sporadically rather than genetically is also a complicating factor.