department of pharmacology

Ruth Keri, Ph.D.

Keri

Professor and Vice Chair
Department of Pharmacology
Associate Director for Basic Research
Case Comprehensive Cancer Center

Phone: (216) 368-3495
Fax: 216-368-1300
E-mail: ruth.keri@case.edu
RT300 Research Tower

Laboratory

Research

 

My laboratory studies the molecular mechanisms through which reproductive hormones and a member of the epidermal growth factor receptor family (Her-2/neu) regulate mammary gland development and breast cancer. Both processes are exquisitely regulated by hormonal input, thus it is likely that many of the events involved in mammary neoplasia are similar to those that occur during normal gland development. Using transgenic mouse models that involve overexpression of an oncogene specifically in the mammary gland, or disruption of the normal hormonal milieu, we are developing in vivo systems to assess the molecular mediators of proliferative or differentiation signals. Furthermore, we have coupled transgenic technology with gene expression microarrays to construct hierarchical pathways of development and oncogenesis. Hypotheses generated from these functional genomics approaches are continually tested using both in vitro cell culture models as well as newly derived transgenic mice. The ultimate goal of this work is to develop a molecular genetic road map of hormone-induced neoplasia with the purpose of identifying novel therapeutic targets for chemotherapy and chemoprevention of breast cancer.




Selected References:

Seachrist, D.D., Johnson, E., Magee, C., Clay, C.M., Graham, J.K., Veeramachaneni, D.N.R., and Keri, R.A., 2012. Overexpression of follistatin in the mouse epididymis disrupts fluid resorption and sperm transit in testicular excurrent ducts. Biol. Reprod., in press.

Sizemore, S.T. and Keri, R.A. The forkhead transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J. Biol. Chem.in press.

Bernardo, G.M., Bebek, G., Ginther, C.L., Sizemore, S.T., Lozada, K.L., Miedler, J.D., Anderson, L.A., Godwin, A.K., Abdul-Karim, F.W., Slamon, D.J., andKeri, R.A. 2012. FOXA1 actively represses the molecular phenotype of basal breast cancer cells. Oncogene, in press.

Peiris, P.M., Bauer, L., Troy, R., Tran, E., Pansky, J., Doolittle, E., Schmidt, E., Hayden, E., Mayer, A., Keri, R.A., Griswold, M.A., and Karathanasis, E. 2012. Enhanced delivery of chemotherapy to tumors using a multi-component nanochain with radiofrequency-tunable drug release. ACS Nano6:4157-4168.

Bernardo, G., and Keri, R.A. 2012. FOXA1: a transcription factor with paralleling functions in development and cancer. Biosci. Rep.32: 113-30.

Beach, J.R., Hussey, G.S., Miller, T.E., Chaudhury, A., Patel, P., Monslow, J., Zheng, Q., Keri, R.A., Reizes, O., Bresnick, A.R., Howe, P.H., and Egelhoff, T.T. 2011. Myosin II Isoform switching mediates invasiveness following TGFβ-induced epithelial-mesenchymal transition. Proc. Natl. Acad. Sci., 108: 17991-17996.

Yori, J.L., Seachrist, D.D., Johnson, E., Lozada, K.L., Abdul-Karim, F.W., Chodosh, L.A., Schiemann, W. P., and Keri, R.A. 2011. Krüppel-like factor 4 Inhibits Tumorigenic Progression and Metastases in a Mouse Model of Breast Cancer. Neoplasia, 13:601-610. Featured on cover.

Lozada, K.L.W., and Keri, R.A. 2011. Bisphenol A increases mammary cancer risk in two distinct murine models of breast cancer. Biol. Reproduction,85:490-497. Featured by F1000 Medicine.

Johnson, E., Seachrist, D.D., DeLeon-Rodriguez, C., Lozada, K.L., Miedler, J., Abdul-Karim, F.W., and Keri, R.A. 2010. HER2/ErbB2-Induced breast cancer cell migration and invasion requires p120 catenin activation of Rac1 and Cdc42. J. Biol. Chem., 285:29491-29501. Featured by F1000.

Montanez-Wiscovich, M.E., Shelton, M.D., Seachrist, D.D., Lozada, K.L., Johnson, E., Miedler, J., Abdul-Karim, F.W., Visvader, J.E., and Keri, R.A. 2010.Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells. J. Pathol.222:271-281.

Bernardo, G., Lozada, K.L., Mosley, J.D., Miedler, J.D., Harburg, G., Asselin-Labat, M.-L., Hewitt, S.C., Godwin, A.K., Korach, K.S., Visvader, J.E., Kaestner, K.H., Abdul-Karim, F.W., Montano, M.M., and Keri, R.A. 2010. FoxA1 is an essential determinant of ER-alpha expression and mammary ductal morphogenesis. Development, 137:2045-2054.

Johnson, E., Seachrist, D.D., DeLeon-Rodriguez, C., Lozada, K.L., Miedler, J., Abdul-Karim, F.W., and Keri, R.A. 2010. HER2/ErbB2-Induced breast cancer cell migration and invasion requires p120 catenin activation of Rac1 and Cdc42. J. Biol. Chem., in press.

Montanez-Wiscovich, M.E., Shelton, M.D., Seachrist, D.D., Lozada, K.L., Johnson, E., Miedler, J., Abdul-Karim, F.W., Visvader, J.E., and Keri, R.A. 2010. Aberrant expression of LMO4 induces centrosome amplification and mitotic spindle abnormalities in breast cancer cells. J. Pathol., in press.

Yori, J.L., Johnson, E., Zhou, G., Jain, M.K., and Keri, R.A. 2010. Kruppel-like factor 4 (KLF4) inhibits epithelial-to-mesenchymal transition through regulation of E- cadherin gene expression. J. Biol. Chem. 285:16854-16863.

Mosley, J.D. and Keri, R.A. 2009. Intrinsic bias in breast cancer gene expression data sets. BMC Cancer, 9:214.

Peters, G.A., Seachrist, D.D., Keri, R.A., and Sen, G.C. 2009. The double-stranded RNA-binding protein, PACT, is required for postnatal anterior pituitary development. Proc. Natl. Acad. Sci., 106:10696-10701.

Montanez-Wiscovich, M.E., Seachrist, D.D., Landis, M.D., Visvader, J., Andersen, B., and Keri, R.A., 2009. LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression. Oncogene, 28:3608-3618.

Mosley, J.D., and Keri, R.A. 2008. Cell cycle correlated genes dictate the prognostic power of breast cancer gene lists. BMC Med. Gen. 1:11.

Milliken, E.L., Lozada, K.L., Johnson, E., Landis, M.D., Seachrist, D.D., Whitten, I., Sutton, A.L.M., Abdul-Karim, F.W., and Keri, R.A. 2007. Ovarian hyperstimulation induces centrosome amplification and aneuploid mammary tumors independently of alterations in p53 in a transgenic mouse model of breast cancer. Oncogene, in press.

vom Saal, F.S., Akingbemi, B.T., Belcher, S.M., Birnbaum, L.S., Crain, D.A., Eriksen, M., Guillette, L.J., Hauser, R., Heindel, J.J., Ho, S-M., Iguchi, T., Jobling, S., Kanno, J., Keri, R.A., Knudsen, K.E., LeBlanc, G.A., Marcus, M., McLachlan, J.A., Myers, J.P., Nadal, A., Newbold, R.R., Olea, N., Prins, G., Richter, C.A., Rubin, B.S., Sonnenschein, C., Soto, A.M., Talsness, C.E., Vandenberg, L.N., Walsen-Kuntz, D.R., Watson, C.S., Welshons, W.V., Wetherill, Y., Zoeller, R.T. 2007. Chapel Hill bisphenol A expert panel consensus statement: Integration of mechanisms, effects in animals and potential to impact human health at current levels of exposure. Reprod. Toxicol.,24:131-138.

Landis, M.D., Seachrist, D.D., Abdul-Karim, F.W., and Keri, R.A. (2006) Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors. Oncogene. 24:5173-5190.

Mosley, J.D., Poirier, J.T., Seachrist, D.D., Landis, M.D., and Keri, R.A. 2007. Rapamycin Inhibits Multiple Stages of c-Neu/ErbB2-induced Tumor Progression in a Transgenic Mouse Model of HER2 Positive Breast Cancer. Mol. Cancer Ther. 6:2188-2197.

Keri, R.A., Ho, S.-M., Hunt, P.A., Knudsen, K.E., Soto, A.M., and Prins, G. 2007. An Evaluation of Evidence for the Carcinogenic Activity of Bisphenol A. Reprod. Toxicol., 24:240-252.

Sutton, A. and Keri, R.A. 2007. The pleiotropic effects of excessive LH secretion in transgenic mice. Semin. Reprod. Med., 25:360-367.

Mosley, J.D. and Keri, R.A. 2006. Splice variants of mIAP1 have an enhanced ability to inhibit apoptosis. Biochem. Biophys. Res. Comm. 348:1174-1183.

Casadesus, G., Milliken, E.L., Webber, K.M., Bowen, R.L., Lei, Z.M., Rao, C.V., Atwood, C.S., Perry, G. Keri, R.A., and Smith, M.A. 2006. Declines in cognitive performance are associated with increased luteinizing hormone levels in mice. Mol. Cell. Endocrinol. 269:107-111.

Landis, M.D., Seachrist, D.D., Montanez-Wiscovich, M.E., Danielpour, D., and Keri, R.A. 2005. Gene expression profiling reveals that mammary tumors induced by erbb2/neu in transgenic mice have undergone alterations in the TGF-beta pathway. Oncogene, 24:5173-5190.
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Milliken, E.L., Zhang, X.-X., Flask, C., Duerk, J.L., MacDonald, P.N., and Keri, R.A. 2005. EB1089, a vitamin D receptor agonist, reduces proliferation and decreases tumor growth rate in a mouse model of hormone-induced mammary cancer. Cancer Lett., 229:205-215.

Knostman, K.A.B., Cho, J.-Y., Ryu, K.-Y., Lin, X., McCubrey,J.A., Hla, T., Liu, C.H., Di Carlo, E., Keri, R.A. , Zhang, M., Hwang, D.Y., Kisseberth, W.C., Capen, C.C., and Jhiang, S.M. (2004) Signaling through 3',5'-cyclic adenosine monophosphate and phosphoinositide-3 kinase induces sodium/iodide symporter expression in breast cancer. J. Clin. Endocrinol. Metab. 89:5196-5203. Download this paper (Adobe PDF).

Mann, R.J., Keri, R.A. , and Nilson, J.H. 2003. Consequences of elevated LH on diverse physiological systems: use of the LH-CTP transgenic mouse as a model of ovarian hyperstimulation-induced pathophysiology. Recent Progress in Hormone Research, 58:343-375.

Kero, J., Savontaus, E., Mikola, M., Pesonen, U., Koulu, M., Keri, R.A. , Nilson, J.H., Poutanen, M., and Huhtaniemi, I. 2003. Obesity in transgenic female mice with constitutively elevated luteinizing hormone secretion. Am. J. Physiol. Endocrinol. Metab. 2003 285:E812-818.

Mikola, M., Kero, J., Nilson, J.H., Keri, R.A. , Poutanen, M., and Huhtaniemi, I. 2003. High levels of luteinizing hormone analog stimulate gonadal and adrenal tumorigenesis in mice transgenic for the mouse inhibin a-subunit promoter/Simian virus 40 T-antigen fusion gene. Oncogene, 22:3269-3278.

Milliken, E.L., Ameduri, R.K., Landis, M.D., Behrooz, A., Abdul-Karim, F.W. and Keri, R.A. 2002. Ovarian hyperstimulation by luteinizing hormone in transgenic mice leads to mammary gland hyperplasia and cancer predisposition. Endocrinol., 143:3671-3680.
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Owens, G.E., Keri, R.A., and Nilson, J.H. 2002. Ovulatory surges of hCG prevent hormone-induced granulosa cell tumor formation and alter specific gene expression profiles. Mol. Endocrinol. 16:1230-1242.
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Hodges, C., Ilagan, A., Jennings, D., Keri, R., Nilson, J., and Hunt, P. 2002. Experimental evidence that changes in oocyte growth influence meiotic chromosome segregation. Hum. Repro. 17:1171-1180.

Quirk, C.C., Lozada, K.L., Keri, R.A. , and Nilson, J.H. 2001. Basal activity and GnRH responsiveness of the LH( promoter in vivo requires a Pitx1 binding site. Mol. Endocrinol. 15:734-746.

Keri, R.A. , Bachmann, D.J., Behrooz, A., Herr, B.D., Ameduri, R.K., Quirk, C.C., and Nilson, J.H. 2000. An NF-Y Binding Site Is Important for Basal, but Not Gonadotropin-releasing Hormone-stimulated, Expression of the Luteinizing Hormone B Subunit Gene. J. Biol. Chem. 275:13082-13088.
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Kero, J., Poutanen, M., Zhang, F.P., Rahman, N., McNichol, A.M., Nilson, J.H., Keri, R.A. , and Huhtaniemi, I.T. 2000. Elevated luteinizing hormone induces expression of its receptor and promotes steroidogenesis in the adrenal cortex. J. Clin. Invest. 105:633-641.
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Keri, R.A. , Lozada, K.L., Abdul-Karim, F.W., Nadeau, J.H., and Nilson, J.H. 2000. Luteinizing hormone induction of ovarian tumors: Oligogenic differences between mouse strains dictates tumor disposition. Proc. Natl. Acad. Sci. USA 97:383-387.
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