Matthew Perez and Erik Christensen

27-hydroxycholestorol (27HC) is a cholesterol metabolite that promotes cell proliferation. Specifically, in this case we are looking at its promotion of ER positive breast tumors. 27HC is an abundant primary metabolite of cholesterol. Because of its relationship with cholesterol it can attach to and actually stimulate estrogen receptors in the body. Since 27HC is a cholesterol metabolite transported in the same lipoprotein particles as cholesterol, there was a positive association between lipoprotein particles and cholesterol [?]. Patients with ER+ breast cancer have higher amounts of 27HC in breast tissue than women who have not been specifically diagnosed with ER+ breast cancer [ref needed]. The amount of 27HC in the breast tumors is even higher in these patients.

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27HC Promotes ER+ Breast Cancer Growth

In order to determine if 27HC was indeed a promoter of ER+ breast cancer a study was conducted to examine whether a human breast cancer cell line, MCF-7, which was transplanted into mice, grew when exposed to various concentrations of 27HC (Nelson, et. al. 2013). Scientists evaluated MCF-7 cell proliferation by quantifying BrdU or 3H-thymidine incorporation. BrdU (Bromodeoxyuridine) is commonly used in the detection of proliferating cells in living tissues because it is readily incorporated into replicating DNA.






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Figure 1. 27HC promotes MCF-7 cell and Ishikawa cell proliferation, and in vivo 27HC stimulates MCF-7 cell xenograft growth and a uterotrophic response. A–D. Cell proliferation was evaluated by quantifying BrdU (A) or 3H-thymidine incorporation (B–D), n= 4–8. A. Growth responses of MCF-7 cells to E2 (10−8M) or 27HC treatment (10−8 to 10−6M) for 24h were compared. B. The dose-response of MCF-7 cells to 27HC (10−9 to 10−6M, for 24h) was determined. C. The requirement for ERα in the growth response of MCF-7 cells to E2 (10−8M) or 27HC (10−6M) was evaluated in cells treated with methyl-piperidino-pyrazole (MPP, 10uM) for 24h. D.

As we can see in Figure 1A, 27HC promotes MCF-7 cell growth. Due to unesterified plasma levels approximating to 10−8M[?], the threshold concentration for activation of MCF-7 cell proliferation was 10−8M. This can be seen in figure 1B.



27HC is Abundant in Normal Breast Tissue

So with this information it would be wise to see the potential impacts of 27HC on ER+ breast cancer. Since 27HC is a cholesterol metabolite transported in the same lipoprotein particles as cholesterol, there was a predictable positive association between serum 27HC and cholesterol in both controls and cancer patients. We can see that this was eventually proven to be true in Figure 2C and 2D. In addition, compared with controls, there was a 3 fold greater 27HC concentration in normal breast tissue from cancer patients than controls. 27HC levels were 2.3 fold higher in the breast tumor itself than in the breast tissue.

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27HC content is increased in normal breast tissue and tumors from ER+ breast cancer patients, and it is locally modulated. A,B. Serum 27HC (A) and total cholesterol concentration (B) in control and breast cancer patients (n= 17 and 58, respectively). Values for 10 cancer patients with serum 27HC greater than 2SD above the mean value for controls are shown in red. C,D. Relationship of serum 27HC to serum cholesterol concentration in controls (C, n=17) and cancer patients (D, n=58). E. 27HC content in normal breast tissue from controls (n=17) and cancer patients (n=48), and in tumors (n=32). *p<0.05 vs control, †p<0.05 vs cancer patient normal breast. F,G. Relationship of normal breast 27HC content to serum 27HC in controls (F, n=17) and cancer patients (G, n=40). H,I. Relationship of tumor 27HC content to serum 27HC (H) or normal breast 27HC content (I) in cancer patients (n=27).

The data presented has presents a couple of main points. First, that the cholesterol metabolite 27HC stimulates MCF-7 cell growth in mice. Secondly, in ER+ breast cancer patients, 27HC content in normal breast tissue is increased compared to cancer-free controls, and tumor 27HC abundance is further increased.

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.
The following references were not cited:
  1. 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.
  2. Umetani, Michihisa, and Philip W. Shaul. "27-Hydroxycholesterol: The First Identified Endogenous SERM." NIH (2011): 1-10. National Institute of Health. Web.
  3. Bianchi F, Kaaks R, Viano H. Overweight, obesity, and cancer risk. Lancet Oncol. 2002; 3:565-574. Web.


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