User:Andrea Danielle Merr
From Proteopedia
Tamoxifen and Breast Cancer
Recent studies have shown that those with high estrogen levels, coupled with an already high risk of developing breast cancer are at a higher risk of the disease occurring. Estrogen is necessary in many areas of the body. Estrogen gives cells permission to grow, including cancer cells. Estrogen is regulated through an activated estrogen receptor transcription factor. These transcription factors in the higher risk patients can activate oncogenes that accelerate cancer cell growth. A new hypothesis suggests that a new way to prevent and treat breast cancer is to change the way estrogen binds to the receptor. The drug Tamoxifen acts as a competitive inhibitor of estrogen and the estrogen receptor. Those with a higher risk of breast cancer that undergo treatment with Tamoxifen show low breast tissue density, which suggests a lower breast cancer risk. Tamoxifen is a smaller molecule that mimics the shape of estrogen, allowing it to bind tightly to the estrogen receptor.
Tamoxifen and the Estrogen Receptor
Tamoxifen lacks the second OH group as well as a tail containing oxygen and nitrogen on the ring. Tamoxifen binds to the ligand binging domain of the estrogen, which leads to a conformational shift. The conformational change causes the helix 12 to shift into an adjacent coactivator. This site is essential for estrogen to do its job. Without the coactivator binding, the receptor remains inactive. The conformational changes occur due to the new hydrophobic interactions between helices 3 and 11. These newly formed hydrophobic interactions lead to a cascade effect of conformational changes across the molecule. The new side chain also causes conformational changes since one of the rings in Tamoxifen is shoved deeper into the pocket. Tamoxifen also provides one less hydrogen bond in the pocket compared to estrogen, causing helices 3, 8, and 11 to extend.
