Location: Cleveland Clinic Main Campus
The Keri Lab focuses on molecularly understanding mammary morphogenesis and carcinogenesis through in vitro and in vivo approaches.
Our mission is to provide key research findings in breast cancer disease for the scientific community and to train the next generation of scientists. We provide care for each other and are fortunate to collaborate with other labs regionally, nationally, and internationally.
Our research is driven by curiosity. This curiosity has allowed us to be open to various biological fields in understanding breast cancer. Traditionally, we are known for investigating the roles of essential transcription factors in mammary gland development and carcinogenesis. Throughout the years we have also expanded to investigating drug cocktails for treating breast cancer, elucidating mechanisms of therapeutic resistance, studying genomic instability,and understanding epigenetic regulation in breast cancer.
I grew up in an Appalachian community in rural Pennsylvania and, with grants and scholarships, attended Edinboro University of Pennsylvania (not the University of Edinburgh in Scotland), earning a BA in chemistry. I became a Research Assistant in the Department of Pharmacology at CWRU and worked in the department for 34 years. I received outstanding mentorship from John Nilson and have held every position in the department other than Chair, including Research Assistant, Graduate Student, Post-doctoral Fellow, Instructor, Assistant, Associate, Full Professor, and Vice Chair. I am also the Associate Director for Basic Research in the Case Comprehensive Cancer Center. My research trajectory began with identifying the basic mechanisms of gene regulation in reproductive biology, specifically the glycoprotein hormones in the pituitary. After a brief stint identifying the role of luteinizing hormone in contributing to granulosa cell tumors of the ovary, I moved into discerning mechanisms underlying breast development and cancer and have been in this field for over 20 years. I have many interests in science, but my core foci are transcriptional and intracellular signaling control of cell states. I am also strongly committed to training the next generation of scientists, particularly those from underserved backgrounds. My mantra is to never give up. If you work hard enough and smart enough, you will be successful!
Mammary Gland Development
Referred to as a malignant caricature of normal mammary development, breast cancer evolves through dysregulation of normal tissue homeostasis. Indeed, many factors that are critical to the development of the nascent mammary gland, such as estrogen and HER2 receptors, have been implicated in breast cancer and have provided targets for drug design. There is considerable similarity in gene expression signatures between breast cancer subtypes and the different stages—or lineages—of mammary epithelial cell development, suggesting that breast cancer subtypes are closely coupled to their developmental cell of origin.
Importantly, each breast cancer subtype displays phenotypic differences and is predictive of patient prognosis. One focus of the Keri lab is to determine the hierarchy of factors that are critical to sustain and/or give rise to each mammary epithelial cell lineage and to understand how each factor impacts the acquisition of the varying cellular properties unique to each breast cancer subtype. Understanding the developmental origins and range of phenotypes unique to each breast cancer subtype will aid in identification of new targets for therapeutic drug design.
Cancer cells acquire the ability to circumvent the normal checks and balances placed on cells, resulting in uncontrolled growth. This is particularly relevant in the case of targeted therapies. While initially a tumor may respond to a particular drug targeting one pathway, eventually the tumor cells find “alternate” pathways to survive.
One focus of the Keri lab attempts to identify combinations of drugs that target intersecting pathways required for breast cancer growth and survival. The PI3K/AKT/mTOR pathway provides the major growth/survival signal in a cell and is one of the most frequently hyperactivated pathways in breast cancer. Drugs targeting this pathway alone have shown limited clinical efficacy, in part, due to loss of pathway feedback inhibition.
We have identified the src-family kinases (SFKs) as members of an intersecting pathway that, when targeted together with the mTOR pathway, have the potential to improve the efficacy of mTOR inhibitors, restoring this feedback control and inducing tumor regression. Future studies are aimed at delineating the precise mechanism of these pathway interactions as well as investigating the utility of this and other drug combinations in multiple types of cancer.
Transcription & Epigenetics
Breast cancer is a heterogeneous disease that can be subdivided into at least six subtypes. These subtypes are defined by their unique gene expression profiles, or transcriptomes. The transcriptomes specific to each subtype of breast cancer are well-characterized, but how these gene expression profiles are controlled remains to be determined. A few transcription factors have been linked to the expression of gene signatures in certain subtypes. However, the master regulatory mechanisms that control these differing phenotypes of breast cancer subtypes are not known.
In both normal cells and cancer cells, cellular phenotypes are not dictated by DNA sequence alone. Epigenetic modifications play a critical role in the regulation of gene expression which in turn dictates how cells behave. Epigenetics refers to various reversible changes to DNA that alter gene expression without changing the DNA sequence. Epigenetic gene regulation plays a critical role in development as well as in disease. In cancer, many epigenetic regulators have been found to be mutated and to drive various cancer types.
Epigenetic modification proteins are currently being studied as potential drug targets. Many drugs have been developed against epigenetic “writers” (proteins that add epigenetic marks), “erasers” (proteins that remove epigenetic marks), and “readers” (proteins that allow the cell to interpret epigenetic marks) and have entered into clinical trials. Our lab is currently investigating a number of drugs targeting the epigenome - in particular, those that inhibit eraser and reader proteins - to determine their efficacy in the most aggressive subtypes of breast cancer. We are also studying a number of epigenetic regulators to elucidate their function in mammary gland development and breast cancer. We hope these studies will lead to a greater understanding of the maintenance of breast cancer transcriptomes and the identification of novel therapeutic targets for the treatment of breast cancer.
View publications for Ruth Keri, PhD
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Tsung, K., Thompson, C.L., Knight, J.M., Maximuk, S., Sadri, N., Gilmore, H., Keri, R.A., Vinayak, S., Harris, L., and Silverman, P. 2018. A breast multidisciplinary genomic tumor board is feasible and can provide timely and impactful recommendations. Breast J., 24:676-677.
Yang, X., Pan, Y., Qiu, Z., Du, Z., Zhang, Y., Fa, P., Gorityala, S., Ma, D., Li, S., Chen, C., Wang, J., Yan, C., Xu, Y, Ruth, K., Ma, Z., and Zhang, J. 2018. RNF126 as a biomarker of poor prognosis in invasive breast cancer and CHK1 inhibitor efficacy in breast cancer cells. Clin. Cancer Res., 24:1629-1643.
Hashemi-Sadrei, N., Muller-Greven, G.M., Ulasov, I., Downs-Kelly, E., Burgett, M.E., Weil, R.J., Du, L., Prayson, R.A., Chao, S., Budd, T.G., Kar, N., Barnholtz-Sloan, J., Nowacki, A.S., Keri, R.A., and Gladson, C.L. 2018. Expression of autophagy-related proteins in metastatic breast cancer to the brain. J. Neurooncol., 140:237-248.
Gayle, S.S., Sahni, J.M., Webb, B., Weber-Bonk, K.L., Shively, M.S., Spina, R., Bar, E.E., Summers, M.K., and Keri, R.A. 2019. Targeting BCL-xL improves the efficacy of bromodomain and extra-terminal protein inhibitors in triple-negative breast cancer by eliciting the death of senescent cells. J. Biol. Chem., 294:875-886.
Thakur, V., Zhang, K., Savadelis, A., Zmina, P., Bonk, K.W., Abdul-Karim, F., Keri, R.A., and Bedogni, B. 2019. The membrane tethered matrix metalloproteinase MT1-MMP triggers an outside-in DNA damage response that impacts chemo- and radiotherapy responses of breast cancer. Cancer Lett., 443:115-124.
Shukla, S., Jandzinski, M., Wang, C., Gong, X., Weber-Bonk, K., Keri, R.A., and Steinmetz, N.F. 2019. A viral nanoparticle cancer vaccine delays tumor progression and prolongs survival in tumor mouse models. Adv. Therap. 1800139.
Adorno-Cruz, V., Hoffmann, A.D., Liu, X., Dashzeveg, N.K., Taftaf, R., Wray, B. Keri, R.A., and Liu, H. 2020. ITGA2 promotes expression of ACLY and CCND1 in enhancing breast cancer stemness and metastasis. Genes and Diseases, https://doi.org/10.1016/j.gendis.2020.01.015.
Roberts, M.S., Sahni, J.M., Schrock, M.S., Piemonte, K.M., Weber-Bonk, K., Seachrist, D.D., Avril, S., Anstine, L.J., Singh, S., Sizemore, S.T., Varadan, V., Summers, M.K., Keri, R.A., 2020. LIN9 and NEK2 are core regulators of mitotic fidelity that can be therapeutically targeted to overcome taxane resistance. Cancer Res., 80:1693-1706.
Roberts, M.S., Finke, V.S., Anstine, L.J., Webb, B.M., Weber-Bonk, K., Seachrist, D.D., and Keri, R.A., 2020. KLF4 dictates erlotinib sensitivity in breast cancer cells through transcriptional repression of epidermal growth factor receptor. Breast Cancer Res., 22:66.
Seachrist, D.D., Hannigan, M.M., Ingles, N.N., Anstine, L.J., Webb, B. Weber-Bonk, K., Guo, Z., Yu, P., Singh, S., Varadan, C., Licatalosi, D.D., Keri, R.A. 2020. The transcriptional repressor BCL11A promotes breast cancer metastasis. J. Biol. Chem, 295:11707-11719.
Turaga, S.M., Silver, D.J., Bayik, D., Paouri, E., Borjini, N., Peng, S., Naik, U., Keri, R.A., Conner, J., Barnholtz-Sloan, J.S., Rubin, J.B., Berens, M., Davalos, D., Lathia, J.D., 2020, JAM-A functions as a female microglial tumor suppressor in glioblastoma. Neuro Oncol., 22:1591-1601.
Cheng, F., Zhao, J., Wang, Y., Lu, W., Liu, Z., Zhou, Y., Martin, W., Wang, R., Huang, J., Hao, T., Yue, H., Ma, J., Hou, Y, Castrillon, J., Fang, J., Lathia, J., Keri, R.A., Lightstone, F.C., Marshall Antman, E., Rabadan, R., Hill, D.E., Eng, C., Vidal, M., Loscalzo, J. Comprehensive characterization of protein-protein interaction network perturbations by human disease mutations. 2020. In press, Nat. Genet.
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Our education and training programs offer hands-on experience at one of the nationʼs top hospitals. Travel, publish in high impact journals and collaborate with investigators to solve real-world biomedical research questions.Learn More
Breast cancer often relies on characteristics of healthy breast cell development, and the developmental regulator TLE3 could play a role in suppressing the spread of breast tumors.
Led by Drs. Keri and Eng, the center will support a multi-investigator research team focused on discerning the role of the tumor microenvironment in breast cancer progression.