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<Structure load='3ert' size='500' frame='true' align='right' caption='Estrogen Receptor Ligand-Binding Domain in Complex with 4-Hydroxytamoxifen' scene='Insert optional scene name here' />

<ref> Bizzini B. Tetanus Toxin. Microbiological Reviews.1979 June;43(2):224-236.[http://www.ncbi.nlm.nih.gov/pmc/articles/PMC281472/pdf/microrev00006-0112.pdf?tool=pmcentrez]</ref>

<ref>PMID:11807088</ref>

== 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. 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 <scene name='Sandbox_Reserved_385/Test_scene/1'>helices 3, 8, and 11</scene> to extend. With the coactivator site blocked, there is a hault in proliferation, meaning that there is no cell growth.
== Tamoxifen, the Drug ==
Tamoxifen is a precursor for the drug that binds to the estrogen receptor, making it a prodrug. The actual drug is 4-hydroxyltamoxifen, which has a greater affinity for the estrogen receptor than Tamoxifen alone. The FDA approved this prodrug 30 years ago to prevent breast cancer in high risk patients. Tamoxifen is classfied as a Seletive Estrogen Receptor Modulator (SERM), meaning that it selectively blocks or activates the activity of estrogen on specific cells, such as breast cancer cells. While Tamoxifen is used to block estrogen acivity in breast cells, it also activates estrogen actrivity in other cells, such as bone and liver cells.

[[Image:estrogen.PNG|The Drug Tamoxifen and the Tamoxifen-Estrogen Complex. The green area represents the change in signal loop due to conformational changes after ligand-binding of Tamoixfen.]]

==References==

<references />

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John Means:

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= Aromatase =
<Structure load='3EQM' size='400' frame='true' align='right' caption='Crystal structure of human placental aromatase cytochrome P450 in complex with androstenedione (PDB entry [http://www.pdb.org/pdb/explore/explore.do?structureId=3EQM])' scene='Insert optional scene name here' />
== Introduction ==
Aromatase belongs to the cytochrome p450 family. During aromatization reactions, Aromatase forms an electron-transfer complex with its partner, NADPH-cytochrome p450 reductase. This enzyme is localized in the endoplasmic reticulum of the cell and tissue specific promoters regulate its activity. <ref> PMID:21125383 </ref> In a number of species, including humans, aromatase can be found throughout the body in places such as the brain, gonads, blood vessels, endometrium, skin, bone and tissues including the placenta and adipose tissue. <ref> PMID: 11427156 </ref> There are many environmental factors that affect the activity of the aromatase enzyme and disrupt its function. Factors that increase the activity of the enzyme include age, obesity, gonadotropins, insulin, anti-m llerian hormone, alcohol and smoking. <ref name="products"> "Aromatase Products" [http://www.novusbio.com/aromatase#13225047480835&ga_enabled%3B0] </ref>

== Function ==
The primary function of Aromatase is to produce estrogens by aromatizing androgens. Aromatase is the only known enzyme in vertebrates capable of catalyzing the aromatization of a six-membered ring <ref name="structure"> Ghosh, D., Griswold, J., Erman, M., Pangborn, W. " X-ray Structure of Human Aromatase Reveals An Androgen-Specific Active Site" [http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2826573/]</ref>. Aromatase converts androstenedione to estrogen and testosterone to estradiol. <ref name="products" /> Aromatase is also a key enzyme in the biosynthesis of estrogens through a process called steroidogenesis. This enzyme helps produce this female sex hormone, estrogen, that helps to fuel the growth of hormone receptor-positive breast cancer.
[[Image:Aromatase_Structure.jpg|thumb|260px|left| Ribbon diagram displaying the overall structure of human placental aromatase. <ref name="structure"/>]]

== Structure==
Due to the membrane-bound nature of mammalian cytochromes P450 (CYP), the structural characterization is extremely difficult. Aromatase is a monomeric enzyme composed of a heme-prosthetic group and a single polypeptide chain consisting of 503 amino-acid residues. <ref name="structure" /> One important feature of CYPs is the iron-containing porphyrin group at the enzyme active site. <ref> PMID: 16395678 </ref> Aromatase is anchored to the endoplasmic reticulum by the amino terminal transmembrane domain. The tertiary structure of Aromatase includes twelve major α-helices and ten β-strands<ref name="structure" />. An androstenedione molecule is bound to the active site of the enzyme. The active site of the enzyme can be found in the distal cavity of the heme-binding pocket. The <scene name='Sandbox_Reserved_382/Heme_iron/3'>heme iron</scene> is within the porphyrin and is considered the reaction center of the enzyme. The <scene name='Sandbox_Reserved_382/Ligand/2'>ligand</scene> is the region attached to the the porphyrin.
'''A ribbon diagram displaying the overall structure of the human placental aromatase is shown to the left.''' The amino terminus starts at residue 45 and is shown in dark blue. The carboxyl terminus ending at residue 496 is shown in red. The helices are labeled A-L and the sheets are labeled 1-10 accordingly. The heme group and the bound ligand are shown in the center of the protein. <ref name="structure" />
== Aromatase Inhibitors ==
Inhibitors of Aromatase stop the estrogen production in post-menopausal women. This action is done by blocking the Aromatase enzyme by turning the hormone, androgen, into small amounts of estrogen. <ref> "Aromatase Inhibitors" [http://www.breastcancer.org/treatment/hormonal/aromatase_inhibitors/] </ref>
There are three Aromatase Inhibitors that are often used in the treatment of breast cancer:
*Arimidex (Anastrozole)
*Aromasin (Exemestane)
*Femara (Letrozole)
Aromatase Inhibitors are unable to stop ovaries from producing estrogen, therefore, these inhibitors only work in post-menopausal women.
== Disorders ==
*'''Aromatase Enzyme Deficiency'''
Aromatase Dificiency is rare in humans, however, if aromatase is nonfunctional due to a mutation estrogen synthesis cannot occur. Affected females are diagnoses at birth because of the obvious characteristics of pseudohermaphroditism. During the childhood of these girls, delayed bone maturation can occur along with cystic ovaries. However, affected males are diagnosed later in life because there are not obvious birth defects. Clincal symptoms such as a tall physique, delayed bone maturation and epiphyseal closure, bone pain, and excess adiposy. <ref> PMID: 17452968 </ref>
*'''Aromatase Excess Syndrome'''
Research shows a rare disorder caused by excessive aromatase activity that can cause familial gynecomastia and feminization of both sexes. This can be inherited by an autosomal dominant manner, affected females and males differently. Females with this disorder showed signs of isosexual precocity and/or macromastia. Males showed characteristics of heterosexual precocity and/or gynecomastia. <ref> PMID: 9543166 </ref>

== References ==
<references/>