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Research Description:
Research in Dr. Nichols' lab involves study of steroid hormone receptors, primarily the estrogen receptors alpha and beta (ERα, ERβ), and their role in normal, as well as in cancer tissue. Dr. Nichols has developed in vitro model systems that allow (a) the analysis of the effect of estrogen receptor (ER) mutations (that we found in breast cancers) on antihormone resistance and (b) screening of novel compounds for ER-subtype selective ligands. Better understanding of ligand activation of ERs may lead to improved endocrine therapies for treating and perhaps preventing breast and other estrogen responsive cancers. Tamoxifen is one of the most effective drugs for treatment and prevention of breast cancer yet a substantial number of breast cancers (30%) fail to respond to tamoxifen or will become resistant, even if they have estrogen receptor (ER+). Dr. Nichols tests the hypothesis that the estrogen receptor, its co-regulator proteins, or their interaction is altered in breast lesions where tamoxifen is ineffective. Tamoxifen therapy (or other selective estrogen receptor modulators- SERMs) requires a functional ER, yet the clinical use of immunohistochemistry is unable to determine function. Coactivators amplify transcription via ER and are the target of antiestrogen inhibition. Dr. Nichols has found changes in ER affecting coactivator binding sites and tamoxifen-induced structure from tumor tissue. One recovered mutation makes tamoxifen a better agonist than estradiol. 
Helix 12, key for transcriptional activity, has an active hormone-bound position, or an inactive antihormone bound position that blocks subsequent coactivator binding, depending on the nature of the bound ligand. (figure from Tanenbaum et al, PNAS USA 95, 5998-6003,1998). Dr. Nichols has a collaboration with Endece Pharmaceuticals for mechanistic analysis of several anticancer drugs. He is testing a parent compound and several of its metabolites in experiments to assess their growth-inhibitory and estrogenic or anti-estrogenic character. They have high likelihood to interact with steroid receptors (most likely estrogen receptors) and with enzymes that metabolize steroids, e.g. aromatase. Dr. Nichols also works with small molecule compounds, 1,1-dichloro-2,2,3-triarylcyclopropanes (DTACs), exhibiting antiestrogenic properties in several assays. He has demonstrated that a subset of these compounds have selectivity for ER alpha or ER beta. In collaboration with Dr. Bino John, we have begun work on an RNA fingerprint of breast cancer that involves computational and experimental work to look at microRNAs and breast cancer. He also develops methods of synthesis for small interfering RNA libraries to discover gene products related to alterable phenotypes.
Education:
B.A. (Biochemistry), University of California, Berkeley.
Ph.D. (Molecular Biophysics & Biochemistry), Yale University.
Postdoctoral Fellow, German Cancer Research Center (DKFZ), Heidelberg.
Important Publications:
- Kim SW, Li Z, Moore PS, Monaghan AP, Chang Y, Nichols M, John B. A sensitive non-radioactive northern blot method to detect small RNAs. Nucleic Acids Res Jan 15 [Epub ahead of print], 2010
- Nichols M and Steinman RA. (2009) A recombinase-based palindrome generator capable of producing randomized shRNA libraries. J Biotechnol 143:79-84, 2009
- Nichols M, Cheng P, Liu Y, Kanterewicz B, Hershberger PA and McCarty Jr KS. Breast-cancer derived M543V mutation in helix 12 of estrogen receptor alpha inverts response to estrogen and SERMs. Breast Cancer Res & Treat June 13 [Epub ahead of print], 2009
- Nichols M. The fight against tamoxifen resistance in breast cancer therapy: A new target in the battle? Molecular Interventions 7:13-16, 2007
- Parise RA, MJ Egorin, B Kanterewicz, AM Lew, SS Chuang, M Nichols, T El-Hefnawy and PA Hershberger. CYP24, the enzyme that catabolizes the anti-proliferative agent vitamin D, is increased in lung cancer. Intl J Cancer 119:1819-1828, 2006
- Hershberger PA, AC Vasquez, B Kanterewicz, S Land, J Siegfried and M Nichols. Regulation of endogenous gene expression in human non-small cell lung cancer cells by estrogen receptor ligands. Cancer Research 65:1598-1605, 2005
- Cheng P, B Kanterewicz, PA Hershberger, KS McCarty, BW Day and M Nichols. Inhibition of ER alpha-mediated transcription by antiestrogenic 1,1-dichloro-2,2,3-triarylcyclopropanes. Molecular Pharm.66:970-977, 2004
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