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ARS Home » Southeast Area » Little Rock, Arkansas » Microbiome and Metabolism Research Unit » Research » Publications at this Location » Publication #151437
Title: OVEREXPRESSION OF THE SP/KLF TRANSCRIPTION FACTOR BTEB1 ALTERS CELL CYCLE PARAMETERS IN MCF-7 BREAST TUMOR CELLS.

Author
item SIMMEN, ROSALIA - UAMS
item EASON, RENEA - ACNC
item VELARDE, MICHAEL - UAMS
item ZHANG, DAYING - UNIV OF FLORIDA
item ZHANG, XUE-LIAN - UNIV OF FLORIDA
item SIMMEN, FRANK - UAMS

Submitted to: American Association of Cancer Research Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 2/10/2003
Publication Date: 3/15/2003
Citation: SIMMEN, R.C., EASON, R.R., VELARDE, M., ZHANG, D., ZHANG, X., SIMMEN, F.A. Overexpression of the Sp/KLF transcription factor BTEB1 alters cell cycle parameters in MCF-7 breast tumor cells.. AMERICAN ASSOCIATION OF CANCER RESEARCH MEETING. 2003. v. 44. p. 539. Abstract No. 2374.

Interpretive Summary: Breast cancer is the second leading cause of cancer deaths, next to lung cancer, in women in the Western hemisphere. In addition, although the exact causes of most breast cancer are unknown, it is thought first develop very early in life (before puberty). Diet is thought to strongly influence the risk of breast cancer and the ACNC is interested in determining if early nutritional interventions will reduce the risk of breast cancer. Abnormal growth and development of the mammary gland underlies breast cancer. Progesterone is a female steroid hormone that regulates proper development of this organ. Loss of function of the nuclear protein that binds progesterone, a protein called progesterone receptor, is likely one of the major causes of breast cancer. This study shows that the progesterone receptor interacts with another nuclear protein called Basic Transcription element Binding Protein-1 (BTEB1) in mammary epithelial cells for proper regulation of cell growth. Thus, further analysis on how these two proteins interact to regulate cell growth may provide an important means to finding how dietary factors, especially those found in infant formula (soy isolfavones, peptides from whey proteins, etc.) reduce cancer risk.

Technical Abstract: In previous work, we determined that forced expression of the Sp-related family member BTEB1 in the human endometrial carcinoma cell line Hec-1-A with low endogenous expression of this protein, resulted in increased cell proliferation which was accompanied by enhanced expression of genes for a number of cell cycle-associated proteins. Moreover, we demonstrated that Hec-1-A sub-lines with higher BTEB1 levels are more responsive to progesterone (P)-dependent progesterone receptor isoform B (PR-B) transactivation, suggesting a role for BTEB1 in the control of hormone-dependent gene transcription. To evaluate whether BTEB1 similarly regulates these processes within the context of mammary epithelium, a known P target in vivo and which expresses this factor, MCF-7 breast tumor cells overexpressing BTEB1 were generated using the Tet-On system. Analysis of clones with increased expression of BTEB1, measured at the level of both gene (tet-BTEB1 chimera) and protein (Western blot) as a result of doxycycline (Dox) induction of rtTA transactivator, revealed an increase in cell proliferation within 24 hr of Dox addition. This was accompanied by the induction of cyclin D1, and paradoxically but similar to that observed for Hec-1-A BTEB1 sub-lines, increased p21/Waf1 and TGF-ß gene expression. Since MCF-7 cells express both PR-A and 'B isoforms, we determined whether cellular BTEB1 levels influenced the responsiveness of known P-dependent target genes to P. RT-PCR analyses indicated that in clones stably transfected with the chimeric BTEB1 construct and in the absence of Dox, the expression of cyclin D1, the tumor suppressor PTEN, and TGF-ß, but not of ß-actin, genes was inhibited by P; these reductions were further enhanced upon addition of Dox to these cells. In contrast, P increased p21 gene expression and this effect was augmented in Dox-treated cells. Taken together, these studies suggest a role for BTEB1 in the control of growth and differentiation of mammary epithelial cells and implicate this transcription factor in hormone-mediated gene transcription, dysregulation of which may contribute to tumorigenesis. (Supported by NIH HD21961 to RCMS and FAS).