Ruth A. Keri, PhD
Associate Director for Basic Researchruth.email@example.com 216.368.3495 (o) 216.368.1300 (f)
Professor and Vice Chair, Pharmacology
Garvin and Frackelton Professor of Cancer Research
Member, Molecular Oncology Program
Dr. Keri came to the Case Comprehensive Cancer Center in 2011 and joined the Department of Pharmacology at Case Western Reserve University School of Medicine in 1992. She received a Bachelor’s degree in chemistry from Edinboro University of Pennsylvania in 1985 and a PhD in pharmacology from Case Western Reserve University in 1992.
My laboratory uses transgenic mouse models coupled with gene expression microarrays to study the molecular mechanisms through which reproductive hormones and Her-2/neu regulate mammary gland development and breast cancer. Because both processes are regulated by hormonal input, it is likely that many of the events involved in mammary neoplasia are similar to those that occur during normal gland development. Hypotheses generated from these functional genomics approaches are continually tested using both in vitro cell culture models and newly derived transgenic mice. Our ultimate goal is to develop a molecular genetic road map of hormone-induced neoplasia so that novel therapeutic targets for breast cancer chemotherapy and chemoprevention can be identified.
Research highlights include:
- We have shown that the factors LMO4, KLF4, FOXA1, FOXC1, and BCL11A each control distinct functions within breast epithelium. My laboratory is the only group that has investigated the roles of FOXA1 and FOXC1 in breast development and our studies revealed that FOXA1 controls transitions between cell states and is an essential mediator of estrogen receptor expression and function in more differentiated breast cancer cells.
- Our novel finding that Src family kinases are essential intermediates in the rebound activation of AKT that occurs with mTOR inhibitors led to the discovery that dasatinib, an SFK inhibitor, greatly potentiates the efficacy of mTOR inhibitors. The Case Comprehensive Cancer Center is developing a Phase I clinical trial to test the efficacy of these combined therapies.
- Our studies have shown that KLF4, one of the Yamanaka factors used for induced pluripotent stem cells, promotes an epithelial state and prevents metastasis. We have also shown that transcription factor FOXC1 promotes breast cancer invasion. We have now transitioned to discovering the genome-wide impact of these factors on the epigenome associated with breast cancer cell states and metastasis.
Basic Research Summary
My laboratory studies how reproductive hormones and genetic factors regulate both normal mammary gland development and the development of breast cancer. Our studies have identified how several genetic factors influence breast cell transition and function in breast cancer and metastasis. Our ultimate goal is to develop a molecular genetic road map of hormone-induced breast cancer so that new chemotherapy and chemoprevention targets can be identified. As a result of our research, the Case Comprehensive Cancer Center is developing a Phase I clinical trial to test whether adding dasatinib, a leukemia treatment, increases the efficacy of currently used chemotherapies in breast cancer.
breast cancer, mammary gland development, transcription factors, hormone-induced neoplasia, KLF4, LMO4, FOXA1, FOXC1, BCL11A, Src kinases, dasatinib
Asrani K, Keri RA, Galidsteo R, Brown S, Horvat S, Ghosh A, Tran N, Winkles J. The HER2- and heregulin β1 (HRG)-inducible TNFR superfamily member Fn14 promotes HER-driven cell migration, invasion and MMP9 expression. Mol Cancer Res. 2013 Apr;11(4):393-404.
Beach JR, Hussey GS, Miller TE, Chaudhury A, Patel P, Monslow J, Zheng Q, Keri RA, Reizes O, Bresnick AR, Howe PH, Egelhoff TT. Myosin II Isoform switching mediates invasiveness following TGF-β-induced epithelial-mesenchymal transition. Proc Natl Acad Sci. 2011 Nov 1;108(44): 17991-6.
Bernardo GM, Bebek G, Ginther CL, Sizemore ST, Lozada KL, Miedler JD, Anderson LA, Godwin AK, Abdul-Karim FW, Slamon DJ, Keri RA. FOXA1 actively represses the molecular phenotype of basal breast cancer cells. Oncogene. 2013 Jan 31;32(5):554-63.
Bernardo G, Keri RA. FOXA1: a transcription factor with paralleling functions in development and cancer. Biosci Rep. 2012 Apr 1;32(2):113-30.
Bernardo G, Lozada KL, Mosley JD, Miedler JD, Harburg G, Asselin-Labat M, Hewitt SC, Godwin AK, Korach KS, Visvader JE, Kaestner KH, Abdul-Karim FW, Montano MM, Keri RA. FoxA1 is an essential determinant of ER-alpha expression and mammary ductal morphogenesis. Development. 2010 Jun;137(12):2045-54.
Han X, Zhang L, Chung J, Pozo FM, Seachrist D, Jacobberger J, Keri R, Gilmore H, Zhang Y. UbcH7 regulates 53BP1 stability and DSB repair. Proc Natl Acad Sci. 2014 Dec 9;111(49):17456-61.
Keri RA, Lozada KL, Abdul-Karim FW, Nadeau JH, Nilson JH. Luteinizing hormone induction of ovarian tumors: oligogenic differences between mouse strains dictates tumor disposition. Proc Natl Acad Sci USA, 2000 Jan 4;97(1):383-7.
Keri RA, Nilson JH. A Steroidogenic Factor-1 binding site is required for activity of the luteinizing hormone b subunit promoter in gonadotropes of transgenic mice. J Biol Chem.1996 May 3;271(18):10782-85.
Keri RA,Wolfe MW, Saunders TL, Anderson I, Kendall SK, Wagner T, Yun J, Gorski J, Nett TM, Camper SA, Nilson JH. 1994. The proximal promoter of the bovine LHb subunit gene confers gonadotrope-specific expression and regulation by GnRH, testosterone, and 17b-estradiol in transgenic mice. Mol Endocrinol. 1994 Dec;8(12):1807-16.
Kero J, Poutanen M, Zhang FP, Rahman N, McNicol AM., Nilson J.H., Keri RA, Huhtaniemi I. 2000. Elevated luteinizing hormone (LH) in transgenic mice induces functional LH receptor expression and steroidogenesis in adrenal cortex. J Clin Invest. 2000 Mar;105(5):633-41.
Landis MD, Seachrist DD, Montanez-Wiscovich ME, Danielpour D, Keri RA.Gene expression profiling of cancer progression reveals intrinsic regulation of transforming growth factor-b signaling in ErbB2/Neu-induced tumors from transgenic mice. Oncogene. 2005 Aug 4;24(33):5173-90.
Weber Lozada K, Keri RA. Bisphenol A increases mammary cancer risk in two distinct murine models of breast cancer. Biol Reproduction. 2011 Sep;85(3):490-97.
Montanez-Wiscovich ME, Seachrist DD, Landis MD, Visvader J, Andersen B, Keri RA. LMO4 is an essential mediator of ErbB2/HER2/Neu-induced breast cancer cell cycle progression. Oncogene. 2009 Oct 15;28(41):3608-18.
Mosley JD, Poirier JT, Seachrist DD, Landis MD, Keri RA. Rapamycin Inhibits Multiple Stages of c-Neu/ErbB2-induced Tumor Progression in a Transgenic Mouse Model of HER2‑Positive Breast Cancer. Mol Cancer Ther. 2007 Aug;6(8):2188-97.
Peiris PM, Bauer L, Toy R, Tran E, Pansky J, Doolittle E, Schmidt E, Hayden E, Mayer A, Keri RA, Griswold MA, Karathanasis E. Enhanced delivery of chemotherapy to tumors using a multi-component nanochain with radiofrequency-tunable drug release. ACS Nano. 2012 May 22;6(5):4157-68.
Peiris PM, Tam M, Vicente P, Abramowski A, Toy R, Bauer L, Mayer A, Pansky J, Doolittle E, Tucci S, Schmidt E, Shoup C, Rao S, Murray K, Gopalakrishnan R, Keri RA, Basilion JP, Griswold MA, Karathanasis E. On-command drug release from nanochains inhibits growth of breast tumors. Pharm Res. 2014 Jun;31(6):1460-8.
Peiris P, Toy R, Doolittle E, Panksy J, Abramowshi A, Tam M, Vicente P, Tran E, Hayden E, Camann A, Erokwu B, Berman Z, Wilson D, Baskaran H, Flask C, Keri RA, Karanthanasis E. Imaging metastasis using an integrin-targeting chain-shaped nanoparticle. ACS Nano 2012 Oct 23;6(10):8783-95.
Seachrist DD, Johnson E, Magee C, Clay CM, Graham JK, Veeramachaneni DNR, Keri RA. Overexpression of follistatin in the mouse epididymis disrupts fluid resorption and sperm transit in testicular excurrent ducts. Biol Reprod. 2012 Aug 23;87(2):41.
Shukla S, Wen AM, Ayat NR, Commandeur U, Gopalkrishnan R, Broome AM, Lozada KW, Keri RA, Steinmetz, NF. Biodistribution and clearance of a filamentous plant virus in healthy and tumor-bearing mice. Nanomedicine. 2014 Feb;9(2):221-35.
Sizemore GM, Sizemore ST, Seachrist DD, Keri RA. 2014. GABA(A) receptor pi (GABRP) stimulates basal-like breast cancer cell migration through activation of extracellular-regulated kinase 1/2 (ERK1/2). J Biol Chem. 2014 Aug 29;289(35):24102-13.
Sizemore GM, Sizemore ST, Pal B, Booth CN, Abdul-Karim FW, Kume T, Keri RA. FOXC1 is enriched in the mammary luminal progenitor population, but is not necessary for mammary ductal morphogenesis. Biol Reprod. 2013 Jul 11;89(1):10.
Sizemore ST, Keri RA. The forkhead transcription factor FOXC1 promotes breast cancer invasion by inducing matrix metalloprotease 7 (MMP7) expression. J Biol Chem. 2012 Jul 13;287(29):24631-40.
Sizemore ST, Sizemore GM, Booth CN, Thompson CL, Silverman P, Bebek G, Abdul-Karim FW, Avril S, Keri RA. Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors. Breast Cancer Res Treat. 2014 Jul;146(1):25-40.
Yori JL, Johnson E, Zhou G, Jain MK, Keri RA. Kruppel-like Factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression. J Biol Chem. 2010 May 28;285(22):16854-63.
Yori JL, Lozada KL, Seachrist DD, Booth C, Abdul-Karim FW, Flask C, Keri RA. Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. Cancer Research. 2014Sep 1;74(17):4762-71.
Yori JL, Seachrist DD, Johnson E, Lozada KL, Abdul-Karim FW, Chodosh LA, Schiemann WP, Keri RA. 2011. Krüppel-like factor 4 Inhibits Tumorigenic Progression and Metastases in a Mouse Model of Breast Cancer. Neoplasia. 2011 Jul;13(7):601-10.