The Liver X Receptor can be selectively modulated in a highly context dependent manner. Here is an example in metastatic lung cancer:
Ma L, Vidana Gamage HE, Tiwari S, Han C, Henn MA, Krawczynska N, Dibaeinia P, Koelwyn GJ, Das Gupta A, Bautista Rivas RO, Wright CL, Xu F, Moore KJ, Sinha S, Nelson ER. The liver x receptor is selectively modulated to differentially alter female mammary metastasis-associated myeloid cells. Endocrinology, 2022 May 15:bqac072. doi: org/10.1210/endocr/bqac072. 163 (7):1-15. Article Link
A Cholesterol metabolite works through the Liver X Receptor in myeloid cells to suppress T cells and promote tumor progression
Ma L., Wang L., Nelson A.T., Han C., He S., Henn M., Menon K., Chen J.J., Baek A.E., Vardanyan A., Shahoei S.H., Park SH., Shapiro D.J., Nanjappa S.G., and Nelson E.R. (2020). 27-Hydroxycholesterol acts on myeloid immune cells to induce T cell dysfunction, promoting breast cancer progression. Cancer Letters, available online: Cancer Letters Article
Link to News Story Highlighting Our Work
He S., Ma L., Baek A.E., Vardanyan A., Vembar V., Chen J.J., Nelson A.T., Burdette J.E., and Nelson E.R. (2019). Host CYP27A1 expression is essential for ovarian cancer progression. Endocrine-Related Cancer 2019 Vol. 26, issue 7
Baek A.E., Yu Y.R., He S., Wardell S.E., Chang C.Y., Kwon S., Pillai R.V., Thompson W., Dubois L.G., Sullivan P.M., Kemper J.K., Gunn M.D., McDonnell D.P., and Nelson E.R. (2017). The cholesterol metabolite 27-hydroxycholesterol facilitates breast cancer metastasis through its actions on immune cells. Nature Communications, 8(1):864. Featured By: Science Daily, Illinois News Bureau, Medical Xpress, Youth Health Magzine, Cardiovascular Business, Gears Of Biz, EurekAlert! etc. PMCID: PMC5636879
Link to Nature Communications Paper
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A cholesterol metabolite induces the secretion of extracellular vesicles that promote tumor growth and progression.
Baek AE, Krawczynska N, Das Gupta A, Dvoretskiy SV, You S, Park J, Deng YH, Sorrells JE, Smith BP, Ma L, Nelson AT, McDowell HB, Sprenger A, Henn MA, Madak-Erdogan Z, Kong H, Boppart SA, Boppart MD, Nelson ER. (2021). The cholesterol metabolite 27-hydroxycholesterol increases the secretion of extracellular vesicles which promote breast cancer progression. Endocrinology. 162(7):bqab095. doi: 10.1210/endocr/bqab095. PMID: 33959755. Featured by Illinois News Bureau (https://news.illinois.edu/view/6367/489696710)
A Cholesterol metabolite works through the estrogen receptor to promote ER+ breast tumor growth.
Nelson E.R., Wardell S.E., Jasper J.S., Park S., Suchindran S., Howe M.K.,Carver N.J., Pillai R.V., Sullivan P.M., Sondhi V., Umetani M., Geradts J., and McDonnell D.P. (2013). 27-Hydroxycholesterol Links Hypercholesterolemia and Breast Cancer Pathophysiology. Science. 342(6162):1094-8. PMCID: PMC3899689. Featured by: New England Journal of Medicine, Science News and Analyses, Nature Reviews Endocrinology, The ASCO Post, The Endocrine Daily Briefing, Ivanhoe Broadcast News, BBC News, The Washington Post, Fox News, Irish Independent, and several other media outlets. Also featured by Faculty 1000 Medicine.
Cholesterol homeostasis in myeloid cells can regulate T cells.
Shahoei, S.H., Kim, Y.C., Cler, S., Ma, L., Anakk, S., Kemper J.K. and Nelson E.R. (2019). Small Heterodimer Partner regulates dichotomous T cell expansion by macrophages. Endocrinology 160(7):1573-1589. Article Link
Development of Novel Cancer Therapeutics
Boudreau MW, Duraki D, Wang L, Mao C, Kim JE, Henn M, Tang B, Fanning SW, Kiefer J, Tarasow TM, Bruckheimer EM, Moreno R, Mousses S, Greene GL, Roy EG, Park BH, Fan TM, Nelson ER, Hergenrother PJ, Shapiro DJ. (2021). A small-molecule activator of the unfolded protein response eradicates human breast tumors in mice. Sci Trans Med. 21;13(603). PMID: 34290053. Selected as Cover Story. Featured by several news outlets (https://news.illinois.edu/view/6367/339688859).
Yu L., Wang L., Maoa C., Duraki D., Kim J.E., Huang R., Helferich W.G. Nelson, E.R., Park B.H., Shapiro D.J. (2019) Estrogen-Independent Myc Overexpression Confers Endocrine Therapy Resistance on Breast Cancer Cells Expressing ERαY537S and ERαD538G Mutations. Cancer Letters. 9: 442:373-382.
Zheng X., Andruska N.D., Lambrecht M.J., He S., Parissenti A., Hergenrother P.J., Nelson E.R., and Shapiro D.J. (2016). Targeting Multidrug-resistant Ovarian Cancer Through Estrogen Receptor α Dependent Hyperactivation of the UPR. Oncotarget. July 24, 2016 issue. PMID: 27463013
Ma, L., Liu, T-W., Wallig, M.A., Dobrucka, I.T. Dobrucki, L.W., Nelson E.R., Swanson, K.S., and Smith A.M. (2016). Efficient Targeting of Adipose Tissue Macrophages in Obesity with Polysaccharide Nano-Carriers. ACS Nano. 10(7):6952-62. PMID: 27281538
Wardell S.E., Nelson E.R., Chao C.A., Alley H.M., and McDonnell D.P. (2015). Evaluation of the pharmacological activities of RAD1901, a selective estrogen receptor degrader. Endocrine Related Cancer. 22(5):713-24. PMCID: PMC4545300. Based on these finding, this compound was positioned for therapy and recently completed a Phase III trial (EMERALD).
Wright T.M., Wardell S.E., Jasper J.S, Stice J.P., Safi R., Nelson E.R., and McDonnell D.P. (2014). Delineation of a FOXA1/ERα/AGR2 regulatory loop that is dysregulated in endocrine resistant breast cancer. Molecular Cancer Research. 12(12); 1829–39. PMCID: PMC4272635. Featured in Editor’s Highlights. Selected for Cover Story.
Safi R., Nelson E.R., Chitneni S.K., Franz K.J., George D.J., Zalutsky M.R., and McDonnell D.P. (2014). The Copper-Signaling Axis as a Target for Prostate Cancer Therapeutics. Cancer Research. 15;74(20):5819-31. PMCID: PMC4203427.
Wardell S.E., Nelson E.R., and McDonnell D.P. (2014). From empirical to mechanism based discovery of clinically useful ER ligands. Steroids. 90:30-8. PMCID: PMC4192009. Invited Review.
Wardell S.E., Nelson E.R., Chao C.A., and McDonnell D.P. (2013). Bazedoxifene exhibits antiestrogenic activity in animal models of tamoxifen resistant breast cancer; implications for treatment of advanced disease. Clinical Cancer Research 1;19(9):2420-31. PMCID: PMC3643989. Featured by: Endocrine Society News Room, DukeHealth.org, Fox News, Express News, About Breast Cancer.com, Toronto Sun and Ivanhoe Broadcast News.