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Steroid receptor crosstalk informs therapies for breast cancer
One of the first clues pathologists look for in tissue from a newly diagnosed breast cancer patient is the estrogen receptor, a nuclear protein that converts hormonal messages in the bloodstream into instructions for the cell. They also look for the presence of the progesterone receptor (PR), but primarily to confirm that the estrogen receptor (ER) is active. In the June 24 issue of Science Advances, a team of researchers led by Geoffrey Greene, Co-director of the Ludwig Center at Chicago, radically upgrade the significance of the progesterone receptor. They show that when exposed to estrogens and progestins, these receptor proteins interact with different sets of binding sites in the cell’s chromosomes, with the progesterone receptor dramatically altering how estrogen receptors interact with the cell’s DNA.
In addition, the researchers inhibited the activities of both receptors with antagonists to see if there would be an added benefit of combining two receptor-selective drugs. Using a well-established ER+/PR+ human breast cancer mouse model, they tested their theory in four groups of mice. One group received a placebo. A second received tamoxifen, an estrogen antagonist routinely used for therapy. The third got an experimental PR antagonist, while the fourth was treated with tamoxifen plus the PR antagonist.
Tumor cells in the placebo-treated mice grew rapidly, to about twice their original size in seven weeks. Tamoxifen, the estrogen antagonist, prevented the tumors from growing but did not cause them to shrink. Used alone, the PR antagonist initially caused the tumors to regress, but tumors began growing again after 35 days. By contrast, the combination of tamoxifen and the PR antagonist caused tumors to shrink dramatically. By day 60, the average tumor volume in these mice had dropped 70 percent.
“These findings,” the authors note, “emphasize the clinical value of assessing both progesterone receptor and estrogen receptor expression in breast cancer samples.” Not only is the progesterone receptor an “essential modulator of estrogen-receptor-regulated genes,” but it also significantly contributes to the “prognostic value of estrogen receptors in ER+/PR+ breast cancers.” In addition, it might serve as an important combinatorial target in these breast cancers.
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