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Loss of the Antiproliferative Gene BTG2 in Estrogen Receptor Positive Breast Carcinoma is Associated with Tumor Grade and Overexpression of Cyclin D1 Protein Hirofumi Kawakubo, Elena Brachtel, Paul Walden and Shyamala Maheswaran Department of Surgical Oncology, Massashusetts General Hospital, Boston, MA 02114 The B-cell Translocation Gene-2 (BTG2) is present in the epithelium of many tissues including the mammary gland where its expression is regulated during glandular proliferation and differentiation in pregnancy. Estrogen and progestin suppress BTG2 expression suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may down-regulate BTG2 in the mammary gland. Expression analysis of BTG2 protein in breast cancer revealed the loss of nuclear expression in 46% of tumors whereas it was readily detectable in the nuclei of adjacent normal glands. Loss of BTG2 in estrogen receptor positive breast tumors correlated significantly with increased histological grade and tumor size. Consistent with its ability to inhibit cyclin D1 transcription, suppression of BTG2 mRNA in the mammary gland during gestation, and by estrogen and progestin correlated with stimulation of cyclin D1. In estrogen receptor positive breast carcinomas, loss of nuclear BTG2 expression demonstrated a significant correlation with cyclin D1 overexpression suggesting that BTG2 may be a factor involved deregulating cyclin D1 expression in breast cancer. Moreover, cyclin D1 reversed BTG2-mediated inhibition of breast cancer cell growth indicating a functional antagonism between the two proteins. Thus coordinated inhibition of BTG2 and enhancement of cyclin D1 would constitute a mechanism to increase estrogen-responsiveness and proliferation in breast cancer cells. 1. Kawakubo, H., Carey, J. L., Brachtel, E., Gupta, V., Green, J. E., Walden, P. D., and Maheswaran, S. (2004). Expression of the NF-kappaB-responsive gene BTG2 is aberrantly regulated in breast cancer. Oncogene 23, 8310-8319. 2. Kawakubo, H., Brachtel, E., Kish, J., Muzikansky, A., Gupta, V., Walden, P. D., and Maheswaran, S. (2005). Loss of BTG2 in estrogen receptor positive breast carcinoma is associated with tumor grade and overexpression of cyclin D1 protein. Oncogene. 3. Hoshiya, Y., Gupta, V., Kawakubo, H., Brachtel, E., Carey, J. L., Sasur, L., Scott, A., Donahoe, P. K., and Maheswaran, S. (2003a). Mullerian inhibiting substance promotes interferon gamma-induced gene expression and apoptosis in breast cancer cells. J Biol Chem 278, 51703-51712. 4. Gupta, V., Carey, J. L., Kawakubo, H., Muzikansky, A., Green, J. E., Donahoe, P. K., MacLaughlin, D. T., and Maheswaran, S. (2005). Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model. Proc Natl Acad Sci U S A 102, 3219-3224. 5. Segev, D. L., Ha, T. U., Tran, T. T., Kenneally, M., Harkin, P., Jung, M., MacLaughlin, D. T., Donahoe, P. K., and Maheswaran, S. (2000). Mullerian inhibiting substance inhibits breast cancer cell growth through an NFkappa B-mediated pathway. J Biol Chem 275, 28371-28379. 6. Segev, D. L., Hoshiya, Y., Hoshiya, M., Tran, T. T., Carey, J. L., Stephen, A. E., MacLaughlin, D. T., Donahoe, P. K., and Maheswaran, S. (2002). Mullerian-inhibiting substance regulates NF-kappa B signaling in the prostate in vitro and in vivo. Proc Natl Acad Sci U S A 99, 239-244. 7. Segev, D. L., Hoshiya, Y., Stephen, A. E., Hoshiya, M., Tran, T. T., MacLaughlin, D. T., Donahoe, P. K., and Maheswaran, S. (2001). Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary epithelial cells in vivo. J Biol Chem 276, 26799-26806 - 68 -
PI3K Targeting by the Beta-GBP Cytokine. Mitogenic Input and Therapeutic Response Livio Mallucci, and Valerie Wells Cell Signaling Laboratory, Pharmaceutical Sciences Research Division, King's College London, Franklin Wilkins Building, 150 Stamford Street, London SE1 9NH, UK. Email: livio.mallucci@kcl.ac.uk Beta-GBP (beta-galactoside binding protein), a newly identified antiproliferative cytokine produced by activated CD4 + and CD8 + T cells, can enforce programmed cell death in cancer cells without harming normal cells. We show that the prime target of beta-GBP activated signaling is the p110 catalytic subunit of PI3 kinase. We find that PI3 kinase has a permissive role in controlling cell cycle and survival signaling and that high mitogenic input, whether endogenous or enforced, facilitates beta-GBP induced apoptosis via inhibition of PI3 kinase activity and consequent inhibition of Ras-ERK and Akt/protein kinase B signaling. References Mallucci L and Wells V (2005) beta-GBP: potential role in cancer therapy. Curr. Opin. Investig. Drugs 6; 1228-1233. Ravatn R et al. (2005) Circumventing multidrug resistance in cancer by beta-galactoside binding protein, an antiproliferative cytokine. Cancer Res. 65; 1631-1634. Mallucci L et al. (2003) Turning cell cycle controller genes into cancer drugs. A role for an antiproliferative cytokine (beta-GBP). Biochem. Pharmacol. 66; 1563-1569. - 69 -
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Table of content PREFACE ..........
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Preface In 1998, we organized the f
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Acknowledgments This meeting has be
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Group B (15h00 - 17h00) Session V.
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- 11 - Exhibition
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Visit our Expo (in alphabetical ord
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Thursday January 26th, 2006 (Early
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Session I : protein domains Poster
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Session II. Receptor signaling and
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VI. Proteasome degradation pathways
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VI. Proteasome degradation pathways
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VIII. Inflammation specific signali
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Session XVI : Chemopreventive agent
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Session XVII : Cell signaling in he
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Dr. Nassera Aouali L-1526 Luxembour
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Dr. Giordano Bianchi Clinic of inte
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Mrs. Isabel Burghardt Laboratory of
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Pr. Czeslaw Cierniewski 92-215 Lodz
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Mr. Igotz Delgado Biochemistry 4894
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Dr. Mark Ginsberg Mail code 0726 92
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Dr. Jochen Hefl Division of Signal
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Mr. Jan Jepsen 2100 Copenhagen DNK
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Pr. Young Min Kim Division of Biolo
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Mr. Christoph Lahtz AG Tumorgenetik
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Mrs. Rasa Merzvinskyte Department o
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