CYP7B1+catabolism+of+27HC

[Some problems viewing the figures on this page.] Matthew Perez and Erik Christensen =What is CYP7B1? =

====CYP7B1 is an enzyme that is used in many different body functions and is best known for its work in bile salt synthesis. However, for our project, we are going to focus on the CYP7B1’s function in the metabolism of estrogen receptor ligands and cholesterol metabolites, such as 27HC. It works to break down such molecules into forms that can no longer be bound to receptors and that are easily excreted from the cell, and eventually the body. Unlike its counterpart CYP7A1, CYP7B1 is an inhibition enzyme, meaning that works to speed the breaking down of molecules. Its counterpart, you will see later in our paper, does the exact opposite. ====

=CYP7B1’s cell proliferation effects in regards to 5α-androstane-3β,17β-diol: =

====Simply put, CYP7B1’s main goal when it comes to 5α-androstane-3β,17β-diol is to preferentially 6ɑ-hydoxylate 5α-androstane-3β,17β-diol, but if that is unavailable, it can also 7ɑ-hydroxylate the molecule. Both hydroxylations have the same effect of inactivating 5α-androstane-3β,17β-diol. The 6ɑ-hydroxylation of 5α-androstane-3β,17β-diol is shown below in the lower part of Figure 1B (Stiles). ====

====The significance of this is that when CYP7B1 is no longer present, problems with uncontrolled cell proliferation begin to arise. One of these problems is an increase in cell proliferation in the breast tissue. In a study done on mice, they found that mice who were missing CYP7B1 were much more likely to see increased cell proliferation in the breast and early onset puberty (Omoto). Figure 2 illustrates these findings, showing greater cell proliferation over two weeks in the CYP7B1 -/- mice as opposed to the control mice, as shown by the increased [|BrdUrd] levels in the mammary tissue(Figure 2I). There were also tests done on the ovarian tissue, but for our purposes we will just be focusing on the mammary tissue. We see that before fifteen weeks, cell proliferation abnormally high. However, once it reaches 15 weeks, the tissue is no longer active and the control mice experience greater proliferation. This is due to the early onset menopause experienced by the CYP7B1 -/- mice (Omoto). This can be explained by the fact that CYP7B1 was absent, causing for growth to be set in overdrive and end much quicker than usual. ====

====What this tells us is that the absence of CYP7B1 causes for greater cell proliferation, which can cause to increased risk for breast cancer. The fact that CYP7B1 is no longer around to control the levels of 5α-androstane-3β,17β-diol means that growth can take place uninhibited. While we may not see women totally lacking CYP7B1, we can deduce that lower than normal levels of the enzyme could also increase the risk for breast cancer. ====

**CYP7B1 and 27HC: **

The other molecule that can be hydroxylated by CYP7B1 is 27HC (Figure 1B top part). 27HC, much like 5α-androstane-3β,17β-diol, is a promoter of cell proliferation. Due to its similarity to estrogen, it has recently been discovered to be a promoter of breast cancer. Recent studies have shown that tumor development in mice without CYP7B1 is much quicker. This is attributed to the fact that CYP7B1-/- mice showed 27HC levels three times higher than the control mice (Nelson). In Figure 5C, we can see that tumor latency was reduced dramatically in CYP7B1 -/- mice, while in Figure 5D, we see tumor growth rates to be much higher in the CYP7B1 -/- mice. Also in Figure 5D, we see an inhibitor of 27HC (ICI 182,780) used, which will be discussed on the following page. These findings about tumor latency and growth offer great insight into a new treatment option for ER positive breast cancer. Also, along with the tests on mice, there have been tests conducted on women who have breast cancer. Researchers measured the levels of CYP7B1 in the breast tissue, finding that women with increased levels of the enzyme had significantly better outcomes and less aggressive tumor growth (Nelson). The fact that this natural enzyme could have such an effect on breast cancer opens up many new avenues for drug development for the treatment of breast cancer.

=__Works Cited: __=
 * 1) Nelson, E. R., S. E. Wardell, J. S. Jasper, S. Park, S. Suchindran, M. K. Howe, N. J. Carver, R. V. Pillai, P. M. Sullivan, V. Sondhi, M. Umetani, J. Geradts, and D. P. Mcdonnell. "27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology." Science 342.6162 (2013): 1094-098. Web.
 * 2) Omoto, Y. "Early Onset of Puberty and Early Ovarian Failure in CYP7B1 Knockout Mice."Proceedings of the National Academy of Sciences 102.8 (2005): 2814-819. Web.
 * 3) Stiles, A. R., J. G. Mcdonald, D. R. Bauman, and D. W. Russell. "CYP7B1: One Cytochrome P450, Two Human Genetic Diseases, and Multiple Physiological Functions." Journal of Biological Chemistry 284.42 (2009): 28485-8489. Web.
 * 4) Wu, Qian, Tomonori Ishikawa, Rosa Sirianni, Hao Tang, Jeffrey G. Mcdonald, Ivan S. Yuhanna, Bonne Thompson, Luc Girard, Chieko Mineo, Rolf A. Brekken, Michihisa Umetani, David M. Euhus, Yang Xie, and Philip W. Shaul. "27-Hydroxycholesterol Promotes Cell-Autonomous, ER-Positive Breast Cancer Growth." Cell Reports 5.3 (2013): 637-45. Web.

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