Promoting+Effects+of+CYP27A1

CYP27A1 is a gene encoding the cytochrome P450 oxidase sometimes referred as sterol 27-hydroxylase. Generally, it is expressed in the macrophages of the cell. We are interested in it because it is required for the conversion of Cholesterol into the metabolite 27HC. Interestingly, no matter whether macrophages of the breast tissue were malignant or benign, they consistently stained positively and strongly for the CYP27A1 protein. With an already established connection between macrophage infiltration and breast cancer (Wu, et al. 2013), researchers were eager to find if there was a deeper connection: macrophage produced 27HC may assist the growth of ER+ breast cancer tumors.

There were a couple of important findings from their research. The first was that (bone derived) macrophages were unable to support MCF7 cell proliferation when treated with CYP27A1 inhibitors. More importantly, introducing 27HC could reverse the effects of the CYP27A1 inhibitors. With the reversal process so effective, this indicated that local production of 27HC by macrophages in the tumor has a high impact on tumor pathology. The second observation was that CYP27A1 was expressed in the cancer cells themselves. From the data, the determination can be made that the expression was based on the size of the tumor. The larger the tumor, the more CYP27A1 expression or, in other words, Overexpression of CYP27A1 increases the likelihood of a higher tumor grade. This can be seen below.



The second main area studied was CYP27A1’s relation to a high cholesterol diet. In order to do this, researchers performed a study on mice where a group of mice was fed a high cholesterol diet from birth and another group on a control diet from birth. In addition to the different diet, both CYP27A1 positive and negative mice were tested on either one diet or another. The results show that CYP27A1 positive mice on a high cholesterol diet developed larger tumors faster and earlier than the mice on the control diet. Furthermore, the tumors were tested and those mice with the high cholesterol diet were found to high much higher levels of 27HC in the tumor than those mice that ate a controlled diet. Most surprisingly, the CYP27A1 negative mice had undetectable levels of 27HC in tumors and tumors formed much later and grew lower. Lastly, if the CYP27A1 negative mice that were fed the control diet were injected with 27HC, they started to produce the same exact results as the CYP27A1 positive mice on the high cholesterol diet.

In my opinion, this is the study’s most significant finding because it indicates that 27HC is the direct breast tumor promoter, moving cholesterol to be an indirect promoter.

References: >
 * 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) 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.
 * 3) Umetani, Michihisa, and Philip W. Shaul. "27-Hydroxycholesterol: The First Identified Endogenous SERM." NIH (2011): 1-10. National Institute of Health. Web.
 * 4) Bianchi F, Kaaks R, Viano H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002; 3:565-574. Web.
 * 5) "CYP27A1 Gene." GeneCards. N.p., n.d. Web. 03 June 2014. .

To navigate back to our Title page, Cholesterol as a Cancer Promoter, Click HERE. Matthew Perez and Erik Christensen