Thresia Thomas
Professor

Estrogens and polyamines in breast cancer cell proliferation and signaling

Breast cancer cell cycle could be stimulated by estradiol and inhibited by antiestrogens. Early studies indicated that estradiol stimulated cell growth as well as antiestrogen-mediated growth inhibition involve events in G1 phase. If characteristics of cell cycle traverse in yeast is conserved in mammalian cells. G1 cyclins should be important in estrogenic stimulation of breast cancer cell growth. In addition. we found that mitotic cyclins are aberrantly expressed in the G1 phase of breast cancer cells. Characterization of the expression and function of cyclins and dependent kinases in breast cancer cell cycle regulation and utilization of this information in development of novel therapeutics for breast cancer is our goal in this area.

Polyamines. putrescine. spermidine and spermine. were discovered nearly 400 years ago. but multiple functions of these molecules are still not clear. Since these molecules are essential for the cell growth and differentiation and increased concentrations of polyamines are found in cancer cells compared to normal cells. polyamines and their biosynthetic enzymes are appropriate targets for development of cancer therapy. Thus polyamine analogs are important in understanding cell growth and differentiation pathways and as therapeutic agents. Our recent observation that polyamines stabilize triplex DNA further provide opportunities for utilizing polyamines in oligonucleotide based therapeutics.

Selected Publications

Sundaresan N, Suresh CH, Thomas T, Thomas TJ, Pillai CK. (2008) Liquid crystalline phase behavior of high molecular weight DNA: A comparative study of the influence of metal ions of different size, charge and binding mode. Biomacromolecules. May 30. [Epub ahead of print]

Vijayanathan V, Greenfield NJ, Thomas TJ, Ivanova MM, Tyulmenkov VV, Klinge CM, Gallo MA, Thomas T. (2007) Effects of estradiol and 4-hydroxytamoxifen on the conformation, thermal stability, and DNA recognition of estrogen receptor beta. Biochem Cell Biol. 85(1):1-10.

Nayvelt I, Thomas T, Thomas TJ. (2007) Mechanistic differences in DNA nanoparticle formation in the presence of oligolysines and poly-L-lysine. Biomacromolecules. 8(2):477-84.

Nair SK, Verma A, Thomas TJ, Chou TC, Gallo MA, Shirahata A, Thomas T. (2007) Synergistic apoptosis of MCF-7 breast cancer cells by 2-methoxyestradiol and bis(ethyl)norspermine.
Cancer Lett. 250(2):311-22.

Sundaresan N. Thomas T. Thomas TJ. Pillai CK. (2006) Lithium ion induced stabilization of the liquid crystalline DNA. Macromol Biosci. 6(1):27-32.

Vijayanathan. V.. Thomas. T. J.. Nair. S. K.. Shrahata. A.. Gallo. M.A.. and Thomas. T. J. (2006) Bending of the estrogen response element by polyamines and estrogen receptors αand β: A fluorescence resonance energy transfer study. Inter. J. Biochem. Cell Biol. 38(7):1191-1206

Vijayanathan. V.. Venkiteswaran. S.. Nair. S. K.. Verma. A.. Thomas. T. J.. and Thomas. T. (2006) Pysiological levels of 2-methoxyestradiol interfere with non-genomic signaling of 17β-estradiol in human breast cancer cells. Clin. Cancer Res. 12(7 Pt 1):2038-48

Balabhadrapathruni. S.. Santhakumaran. L.M. Thomas. T.J. Shirahata. A.. Gallo. M.A (2005) Thomas. T. (2005) Bis(ethyl)norspermine potentiates the apoptotic activity of the pure antiestrogen ICI 182780 in breast cancer cells. Oncol Rep. 13:101-108.

Lewis. J. S.. Thomas. T. J.. Pestell. R. G.. Albanese. C.. Gallo. M. A. (2005) Thomas Differential effects of 16alpha-hydroxyestrone and 2-methoxyestradiol on cyclin D1 involving the transcription factor ATF-2 in MCF-7 breast cancer cells. J. Mol. Endocrinol. 34:91-105.

Vijayanathan. V.. Lyall. J.. Thomas. T.. Shirahata. A.. Thomas. T. J. (2005) Ionic. structural. and temperature effects on DNA nanoparticles formed by natural and synthetic polyamines. Biomacromolecules. 6:1097-1103.

Venkiteswaran. S.. Vijayanathan. V.. Shirahata. A.. Thomas. T.. Thomas. T. J. (2005) Antisense recognition of the HER-2 mRNA: effects of phosphorothioate substitution and polyamines on DNA.RNA. RNA.RNA. and DNA.DNA duplex stability. Biochemistry 44:303-312.

Lewis. J. S.. Vijayanathan. V.. Thomas. T. J.. Pestell. R. G.. Albanese. C.. Gallo. M.A.. and Thomas. T. (2005). Activation of cyclin D1 by estradiol and spermine in MCF-7 breast cancer cells: A mechanism involving the p38 MAP kinase and phosphorylation of ATF-2. Oncology Res. 15:113-128.

Nair. S. K.. Thomas. T. J.. Greenfield. N. J.. Chen. A.. He. H.. Thomas. T. (2005) Conformational dynamics of estrogen receptors alpha and beta as revealed by intrinsic tryptophan fluorescence and circular dichroism. J. Mol. Endocrinol. 35:211-223.

Thomas. T.. Gallo. M.A. and Thomas. T. J. (2004) Estrogen receptors as targets for drug development for breast cancer. osteoporosis and cardiovascular diseases. Current Cancer Drug Targets 4:483-499.