Exposure to high levels of estrogen in the mother’s womb may be linked to resistance to tamoxifen therapy in estrogen receptor (ER)-positive breast cancers, according to the results of a recent animal study.
The study, “Effects of In Utero Exposure to Ethinyl Estradiol on Tamoxifen Resistance and Breast Cancer Recurrence in a Preclinical Model,” published in the Journal of the National Cancer Institute, showed that in utero estrogen exposure causes epigenetic changes in four genes linked to tamoxifen resistance. But the researchers think this effect can be reversed with epigenetic modifying drugs, such as Depakene (valproic acid) or Apresoline (hydralazine).
“Higher estrogen levels in utero have been known to increase risk of estrogen positive breast cancer in laboratory animals — and humans — but it wasn’t known until this study that these elevated levels may also be responsible for tamoxifen resistance,” Leena Hilakivi-Clarke, PhD, a professor of oncology at Georgetown University’s Lombardi Comprehensive Cancer Center, and the study’s co-lead author, said in a press release.
Elevated estrogen during pregnancy is known to increase breast cancer risk in several subsequent generations. Because previous studies have shown that this occurs through epigenetic changes (modifications in the DNA that change the expression rates of specific genes) in the offspring’s mammary glands, the researchers thought that these epigenetic changes could be affecting the way tumors responded to treatment.
To test their hypothesis, the researchers added an endocrine disrupting chemical, ethinyl estradiol (EE2), to the drinking water of pregnant rats. They then induced mammary tumors in the female offspring of the treated rats and in control rats (whose mothers had not been exposed to EE2).
They found that rats born to EE2-exposed females were significantly less likely to respond to tamoxifen treatment. In rats that showed complete response to tamoxifen, the EE2-offspring were seen to be two times more likely to acquire resistance to treatment and to have their cancer reappearing.
“Everyone is exposed to some environmental estrogens, and many pregnant women naturally produce a lot of this hormone,” said Hilakivi-Clarke. “The exposures may pose risks both in terms of breast cancer risk and tamoxifen resistance.”
The researchers found these complications correlated with epigenetic changes in four particular genes in the EE2 offspring. But Depakene and Apresoline treatment reversed these changes, and reduced resistance to tamoxifen treatment in EE2 progeny. Depakene and Apresoline are two approved drugs indicated for epileptic and hypertension patients, respectively.
“We have found that the same genes responsible for tamoxifen resistance in our animals are also turned off in human breast cancer cells that do not respond to the drug,” said Hilakivi-Clarke. “Because these genes were epigenetically silenced — meaning they were not irreversibly altered, just switched off — it was possible to turn them back on. It remains to be determined if these genes are markers of in utero estrogen exposure in breast cancer patients.”
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