Tamoxifen: Difference between revisions
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<StructureSection load='3ert' size=' | <StructureSection load='3ert' size='450' side='' caption='Estrogen Receptor Ligand-Binding Domain in Complex with 4-Hydroxytamoxifen (PDB code [[3ert]])'> | ||
[[Image:tam.png|thumb| | [[Image:tam.png|thumb|250px|left|Prodrug Tamoxifen]] | ||
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Recent studies have shown that men and women with high estrogen levels, coupled with an already high risk of developing breast [[cancer]], are at a higher risk of the disease occurring.<ref name="danielle">Skafar, D., and S. Koide. "Understanding the Human Estrogen Receptor-alpha Using Targeted Mutagenesis." Molecular and Cellular Endocrinology 246.1-2 (2006): 83-90. </ref> Estrogen is necessary in many areas of the body. It 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 recent hypothesis suggests that a new way to prevent and treat breast cancer is to change the way estrogen binds to the receptor. The [[Pharmaceutical Drugs|drug]] Tamoxifen acts as a competitive inhibitor of estrogen and the [[Estrogen receptor]]. Those with a higher risk of breast cancer who 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. | Recent studies have shown that men and women with high estrogen levels, coupled with an already high risk of developing breast [[cancer]], are at a higher risk of the disease occurring.<ref name="danielle">Skafar, D., and S. Koide. "Understanding the Human Estrogen Receptor-alpha Using Targeted Mutagenesis." Molecular and Cellular Endocrinology 246.1-2 (2006): 83-90. </ref> Estrogen is necessary in many areas of the body. It 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 recent hypothesis suggests that a new way to prevent and treat breast cancer is to change the way estrogen binds to the receptor. The [[Pharmaceutical Drugs|drug]] Tamoxifen acts as a competitive inhibitor of estrogen and the [[Estrogen receptor]]. Those with a higher risk of breast cancer who 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. | ||
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== Tamoxifen and 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.<ref name="danielle" /> Tamoxifen binds to the ligand binging domain of the estrogen receptor, which leads to a conformational shift.<ref name="danielle" /> The conformational change causes the <scene name='Sandbox_Reserved_385/12_helix_er/1'>helix 12</scene> to shift into an adjacent coactivator.<ref>Pecorak, Sara, and Tom Susman. "Tamoxifen, Diethylstilbesterol and the Estrogen Receptor Ligand Binding Region." (04). Web. <http://biology.kenyon.edu/BMB/Chime2/2001/estrogen/FRAMES/start.htm>.</ref> This site is essential for estrogen to do its job. Without the coactivator binding, the receptor remains inactive. Conformational changes also 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. With the coactivator site blocked, there is a halt in proliferation, meaning that there is no cell growth. | Tamoxifen lacks the second OH group as well as a tail containing oxygen and nitrogen on the ring.<ref name="danielle" /> Tamoxifen binds to the ligand binging domain of the estrogen receptor, which leads to a conformational shift.<ref name="danielle" /> The conformational change causes the <scene name='Sandbox_Reserved_385/12_helix_er/1'>helix 12</scene> to shift into an adjacent coactivator.<ref>Pecorak, Sara, and Tom Susman. "Tamoxifen, Diethylstilbesterol and the Estrogen Receptor Ligand Binding Region." (04). Web. <http://biology.kenyon.edu/BMB/Chime2/2001/estrogen/FRAMES/start.htm>.</ref> This site is essential for estrogen to do its job. Without the coactivator binding, the receptor remains inactive. Conformational changes also 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. With the coactivator site blocked, there is a halt in proliferation, meaning that there is no cell growth. | ||
== Tamoxifen and the Estrogen-related receptor == | |||
<scene name='50/501401/Cv/4'>Binding of nuclear receptor corepressor 2 peptide and 4-hydroxytamoxifen</scene> to human estrogen-related receptor γ. The chemotherapeutic drugs bisphenol and <scene name='50/501401/Cv/5'>tamoxifen</scene> are nestled between 4 alpha helices in the ERR active site <ref>PMID:16990259</ref>. | |||
== Tamoxifen, the Drug == | == Tamoxifen, the Drug == | ||