Tumor cells in the placebo-treated mice grew rapidly. Tamoxifen prevented the tumors from growing. CDB4124 initially caused the tumors to regress, but after 35 days, the tumors began growing again. The combination of tamoxifen and CDB4124 caused tumors to shrink 70 percent by day 60. Credit: The Greene Laboratory
One of the first clues pathologists look for in tissue from a newly diagnosed breast cancer patient is the estrogen receptor. They also look for the presence of progesterone receptors, primarily to confirm that the estrogen receptor is active. In the June 24 issue of Science Advances, however, researchers radically upgrade the significance of the progesterone receptor.
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. This observation is important as >2/3 of breast cancers contain both estrogen and progesterone receptors.
Previous studies showed that when exposed to estradiol, the estrogen receptor activates genes that encourage tumor cells to grow and divide. “Our study, as well as that of the Cambridge group, showed that when progesterone or a progestin is added, it changes the landscape in the nucleus,” Greene said. “It opens up a whole new set of binding sites for the estrogen receptor that now work in conjunction with the progesterone receptor.” This combination inhibits cellular proliferation, cell survival and pathways involved in metastasis.
“Our data further suggest that, despite the historical bias toward the effects of estrogen on the estrogen receptor, it’s the progesterone receptor that dominantly controls estrogen receptor activity when both receptors are present and activated.”
Building on the well-established use of tamoxifen, an estrogen antagonist, they decided to inhibit the activities of both receptors with antagonists to see if there would be an added benefit of combining 2 receptor-selective drugs. Using a well-established ER+/PR+ human breast cancer model (T47D) implanted in immune-compromised mice, they tested their theory in 4 groups. 1 group received a placebo. A 2nd group received tamoxifen. The 3rd group was treated with a progesterone receptor antagonist, an experimental drug known as CDB4124 (Telapristone). The 4th group was treated with tamoxifen plus CDB4124 to simultaneously block both the estrogen and progesterone receptors.
Tumor cells in the placebo-treated mice grew rapidly, to ~200% of their original size in 7 weeks. Tamoxifen prevented the tumors from growing but did not cause them to shrink. CDB4124, the progestin antagonist, initially caused the tumors to regress, but after 35 days, the tumors began growing again; by 7 weeks they were about 50% larger than their original size. The combination of tamoxifen + CDB4124 caused “virtually full regression” Singhal said. By day 60, the average tumor volume was 70% lower than the original tumors.
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. http://www.eurekalert.org/pub_releases/2016-06/uocm-ctb062216.php
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