The long-range objective of Dr. Tekmalís research is to elucidate the role of hormones and growth factors and their receptors in the etiology of breast cancer and gynecological cancers as well as in endometriosis. Basic, pre-clinical and translational research uses both in vitro and in vivo model systems as well as human subjects.

Breast Cancer: We have recently showed that the cellular gene aromatase overexpression is responsible for tumor cell proliferation. Aromatase catalyzes the conversion of androgens to estrogen, which is the rate-limiting step in estrogen biosynthesis. Recent studies suggest that the in situ aromatase/breast estrogen may play a role in breast cancer. To directly test the role of breast tissue estrogen in initiation of breast cancer, we have developed the aromatase transgenic mice model, and demonstrated for the first time that increased mammary estrogens due to the overexpression of aromatase in female mammary glands leads to the induction of various preneoplastic and neoplastic changes that are similar to early breast cancer. On going studies are aimed at further investigating: does increased mammary estrogen act synergistically with oncogenes, growth factors, and tumor suppressor genes to initiate/promote breast cancer; does mammary estrogen plays a role in regulating genes involved in programmed cell death; are these animals susceptible to carcinogens; and does blocking estrogenic effect by therapeutic intervention results in the prevention of preneoplastic/neoplastic changes, in turn, reducing the risk of developing breast cancer.

Cervical Cancer: We are also first one to show that aromatase is overexpressed in some cervical tumor suggesting an in situ role for tissue estrogen in cervical malignancy. On going studies are aimed at further investigating the importance of tissue estrogen in cervical malignancy using both in vitro and in vivo model systems.

Interaction of Growth factors with steroid hormones: The majority of invasive breast, ovarian, and endometrial cancers express both macrophage colony stimulating factor -1 (CSF-1) and its receptor, c-fms. The pattern of expression of these genes in the same cell/tumors of malignant phenotypes and in benign disease conditions suggest that the concomitant expression of CSF-1 and c-fms may contribute to tumorigenesis. Our current studies have shown that CSF-1 is an autocrine factor for the proliferation of endometrial cells and oxidative stress affects its regulation. Using an in vivo transgenic animal model we have also demonstrated that these genes play significant role in the initiation of breast and ovarian cancer. Further more we have shown CSF-1 and c-fms also plays an important in cervical malignancies. Steroid hormones like estrogen and progesterone upregulate c-fms a receptor for CSF-1 resulting in initiation of CSF-1/c-fms signal transduction and downstream effects.

Research in this laboratory involves a combination of skills using molecular biology, tumor biology, molecular endocrinology that employs preclinical animal models of human disease as well as human clinical subjects. These projects provide an opportunity to understand the etiology of various cancers and reproductive disorders that affect womenís health as well as gain experience in the designing and testing of various therapeutic and prevention approaches.

Tekmal, R.R., Burns, W. N., Rao, D.V., Montoya, I., Chang., P., Stoica, G. and Schenken, R.S.: Regulation of granulosa cell "-inhibin expression by luteinizing hormone and steroids. Am. J. Obst. Gynecol. 175: 420-427, 1996.

Mandava, U., Kirma, N., and. Tekmal, R. R.: Aromatase overexpression transgenic mice model: Cell type specific expression and use of letrozole to abrogate mammary hyperplasia without affecting normal physiology J. Steroid Biochem. Mol. Bio. 79: 27-34, 2001

Luthra, R., Kirma, N., Jones J., and Tekmal, R.R.: Use of letrozole as a chemopreventive agent in aromatase overexpressing transgenic mice. J. Steroid Biochem. Mol. Biol. 86: 461-465, 2003.

Tekmal, R.R., Liu, Ya-Guang., Jones, J., Lubahn D.B., Korach, K.S., and Kirma, N.: Estrogen receptor alpha is required for the mammary development and the induction of mammary hyperplasia and epigenetic alterations in the aromatase transgenic mice. J. Steroid Biochem. Mol. Biol. May 2005. (online from June 11 PMID: 15955696).