Increased Estrogen Levels In Utero Linked to Breast Cancer Chemotherapy Resistance

New mouse study suggests that exposure to endocrine disrupting chemicals may cause resistance to tamoxifen therapy in some breast cancers.

In utero exposure to endocrine-disrupting chemicals may be where tamoxifen resistance originates in estrogen receptor positive breast cancers, a recent analysis indicates.

In a study published in the Journal of the National Cancer Institute (JNCI), researchers compared the results obtained from an animal model, in human breast cancer cells grown in culture, and in publically available datasets collected from thousands of estrogen receptor positive breast cancer patients treated with tamoxifen.

By doing so, researchers were able to identify 4 genes linked to tamoxifen-resistance and poor prognosis.

“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,” said study co-lead author Leena Hilakivi-Clarke, PhD.

Upon further investigation, researchers were able to demonstrate that changes in these genes were reversed by adding well-tolerated epigenetic modifying drugs, hydralazine, and valproic acid, to tamoxifen therapy regimen.

The results of the study showed that the drugs were able to prevent resistance to tamoxifen, as well as the recurrence of breast cancer in the animal model.

“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,” Hilakivi-Clarke said. “Because these genes are 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.

“Tamoxifen is an excellent agent to use to both prevent breast cancer in high-risk women, and to reduce cancer recurrence in women who develop tumors, so our goal is to ensure that patients who use this drug can respond to it.”

Authors noted that the animal model they used was the same used more than 40 years ago to discover that tamoxifen prevents breast cancer. However, it was used for the first time in the current study to examine factors that cause estrogen receptor positive breast cancer to recur during tamoxifen therapy.

To conduct the study, researchers used an endocrine-disrupting chemical called ethinyl estradiol (EE2), which is present at low levels in drinking water, and is also an ingredient in hormone replacement therapy and birth control pills.

“Everyone is exposed to some environmental estrogens, and many pregnant women naturally produce a lot of this hormone,” Hilakivi-Clarke said. “The exposures may pose risks both in terms of breast cancer risk and tamoxifen resistance.”