Department of Cellular Biology and Anatomy
Department of Radiology
Department of Surgery
Research Office CB1815
Research Lab R&E Building CB2312
Office phone: 706-721-1876
Laboratory phone: 706-721-1876
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Current Members of the Schoenlein lab:
Natasha Culpepper, Student Assistant
Carol Joseph, STAR Student
Allison Lewis, STAR Student
Our overall goal is to improve the treatment of estrogen receptor positive breast cancer such that the patient is cured of the disease. Approximately 70% of breast cancers express the estrogen receptor (ER). Binding of the hormone estrogen to the ER activates the receptor and, ultimately, stimulates the growth of ER-expressing breast cancer cells. Current treatments for ER-expressing breast cancers rely on antiestrogens such as selective estrogen receptor modifiers or aromatase inhibitors to block the growth-promoting effects of estrogen. However, the use of antiestrogens offers a clinical benefit to only one-half of patients with ER+ breast cancer due to either the occurrence of intrinsic or acquired antiestrogen resistance. In pre-clinical studies, our laboratory has identified two combined treatment approaches (the antiestrogen TAM plus the antiprogestin RU486 and TAM plus the proteasome inhibitor Velcade) that more effectively kill breast cancer cells than antiestrogen treatment alone. The underlying mechanism of the increased cytotoxic action of these combined therapies is being identified in our laboratory. In part, these combined therapies more effectively block the pro-survival role of autophagy. Autophagy is a stress response that normal and cancer cells induce in response to various stress factors, i.e. nutrient deprivation, ionizing radiation, and multiple drug treatments, to facilitate their survival. During autophagic catabolism, both proteins and organelles such as damaged mitochondria can be degraded, generating important molecules that can be recycled and utilized by the cell for survival or reducing reactive oxygen species that can kill the cell, respectively. Our laboratory was the first to show that autophagy was required for ER+ breast cancer cells to develop antiestrogen resistance and that the proteasome inhibitor Velcade can also be used to block autophagy function in stressed, surviving cancer cells. We predict that Velcade can be used as an effective autophagy inhibitor in all “stressed” cancer cells that utilize autophagy as a survival pathway and our current studies are testing this hypothesis. Our current research is also elucidating key molecules involved in pro-survival autophagy in order to identify new molecular targets for the treatment of breast cancer. In the Figure, autophagosome within the cytosol of MCF-7 breast cancer cells are stained blue-green in a novel antiestrogen-resistant mutant (selected in the Schoenlein laboratory) that utilizes autophagy to escape antiestrogen induced cell death. In this mutant, blocking autophagosome function during antiestrogen therapy induces apoptosis.
We use several breast cancer models for in vitro (cell culture) and in vivo (human tumors inoculated into the mammary fat pads of nude mice) pre-clinical studies that include molecular, biochemical, histological, and imaging methods.
Gaddy VT, Barrett JT, Delk JN, Kallab AM, Porter AG, Schoenlein PV. Mifepristone induces growth arrest, caspase activation, and apoptosis of estrogen receptor-expressing, antiestrogen-resistant breast cancer cells. Clin Cancer Res. 15: 5215-5225, 2004.
Schoenlein PV, Hou M, Samaddar JS, Gaddy VT, Thangaraju M, Lewis J, Johnson M, Ganapathy V, Kallab A, Barrett JT. Downregulation of retinoblastoma protein is involved in the enhanced cytotoxicity of 4-hydroxytamoxifen plus mifepristone combination therapy versus antiestrogen monotherapy of human breast cancer. Int. J. Oncol. 31: 643-655, 2007.
Samaddar, J.S., Gaddy, V.T., Duplantier, J., Thandavan, Periyasamy Thandavan, S., Shah, M., Smith, M., Browning, D., Rawson, J., Smith, S., Barrett, J. and Schoenlein, P. V. A role for macroautophagy in protection against antiestrogen-induced cell death and the development of antiestrogen resistance. Molec.Cancer Ther 7:2977-2987, 2008.
Schoenlein, P. V., Periyasamy-Thandavan, S., Samaddar, J. S., Jackson, W.H., and Barrett, J. T. Autophagy facilitates the progression of ERα-positive breast cancer cells to antiestrogen resistance. Autophagy 5: 400- 403, 2009.
Periyasamy-Thandavan, S., Jackson, W. H., Erickson, B., Barrett, J. R., Hill, W., Elangovan, G., Ganapathy, V., Bhalla, K. and Schoenlein, P. V. Proteasome inhibition blocks the catabolic process of autophagy, affects an ER stress response, and induces cell death in antiestrogen-sensitive and –resistant ER+ breast cancer cells. Autophagy 6:19-35, 2010.
Periyasaym-Thandavan, S, Takhar, S, Singer A, Dohn, M, Jackson, WH, Welborn, AE, LeRoith, D, Marrero M, Huang S and Schoenlein P. V. IGF-1 attenuates antiestrogen- and antiprogestin-induced apoptosis in ER+ breast cancer cells by MEK1 regulation of the BH3-only pro-apoptotic protein Bim. Submitted, Reviewed and In revision