Visit our Expo - Redox and Inflammation signaling 2012

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
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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.
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Donahoe, P. K., and Maheswaran, S. (2000). Mullerian inhibiting substance inhibits breast cancer cell growth
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Maheswaran, S. (2001). Mullerian inhibiting substance regulates NFkappaB signaling and growth of mammary
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