Estrogens play essential roles in reproduction and contribute to the pathophysiology of breast cancer. Synthesis of estrogens from C19-steroids is catalyzed by aromatase P450 (product of the CYP19 gene). In humans, estrogens are produced in gonads, brain, placenta, bone, adipose stromal and vascular cells. Aromatase also is upregulated in breast tumors and surrounding adipose stromal cells. Expression of aromatase in each of these tissues is controlled by unique promoters that lie upstream of tissue-specific first exons that are alternatively spliced onto a common site in exon II. Interestingly, in adipose stromal cells surrounding breast tumors, switching from the weak adipose-specific promoter (promoter 1.4) to the strong ovary-specific promoter (promoter lla) occurs. During the past four years, we have successfully utilized transgenic mice to define discrete genomic regions that mediate tissue-specific human (h)CYP19 expression in placenta, ovary and brain. In cultured human trophoblast cells, we found that syncytiotrophoblast differentiation and induction of hCYPW expression are O2-dependent, and have identified response elements and transcription factors that mediate these effects and the mechanisms for O2 regulation. In the proposed research, we will continue to define critical response elements and transcription factors that mediate placenta (promoter 1.1)-, ovary- and brain (promoter 1f)-specific hCYPW expression. Our findings also indicate that the orphan nuclear receptor, LRH-1, may play an important role in gonadal development and estrogen synthesis by the ovary during the estrous cycle and pregnancy. We, therefore, will continue to assess the importance LRH-1 and other transcription factors in the regulation of CYP19 gene expression in ovary during the estrous cycle and pregnancy and in postnatal estrogen biosynthesis. We recently discovered that hCYP19 expression in breast cancer cells is greatly induced by cytokines and inhibited by progesterone acting through the progesterone receptor (PR). In the proposed research, the mechanisms for activation of hCYPW expression in breast cancer cells by inflammatory mediators, growth factors and estrogen, and for inhibition by PR will be determined. Levels of hCYP19 and cyclooxygenase-2 mRNA in human breast tumors and cell lines will be correlated with expression of estrogen receptors, PR and PR isoforms, PR-A, PR-B and PR-C, and with markers of tumor aggressiveness. The potential inhibitory role of PR on expression of hCYP19, growth factor receptors and progression to cancer also will be assessed in mice with a mammary -specific knockout of PR. We believe that this research will provide important insight into tissue-specific regulation of aromatase in normal physiology and in pathophysiologic states.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK031206-24
Application #
7274329
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Margolis, Ronald N
Project Start
1983-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
24
Fiscal Year
2007
Total Cost
$327,502
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Biochemistry
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Muralimanoharan, Sribalasubashini; Kwak, Youn-Tae; Mendelson, Carole R (2018) Redox-Sensitive Transcription Factor NRF2 Enhances Trophoblast Differentiation via Induction of miR-1246 and Aromatase. Endocrinology 159:2022-2033
Zhang, Ming; Muralimanoharan, Sribalasubashini; Wortman, Alison C et al. (2016) Primate-specific miR-515 family members inhibit key genes in human trophoblast differentiation and are upregulated in preeclampsia. Proc Natl Acad Sci U S A 113:E7069-E7076
Luo, Yanmin; Kumar, Premlata; Chen, Chien-Cheng et al. (2014) Estrogen-related receptor ? serves a role in blood pressure homeostasis during pregnancy. Mol Endocrinol 28:965-75
Mendelson, Carole R (2013) GRTH: a key to understanding androgen-mediated germ cell signaling. Endocrinology 154:1967-9
Luo, Yanmin; Kumar, Premlata; Mendelson, Carole R (2013) Estrogen-related receptor ? (ERR?) regulates oxygen-dependent expression of voltage-gated potassium (K+) channels and tissue kallikrein during human trophoblast differentiation. Mol Endocrinol 27:940-52
Kumar, Premlata; Luo, Yanmin; Tudela, Carmen et al. (2013) The c-Myc-regulated microRNA-17~92 (miR-17~92) and miR-106a~363 clusters target hCYP19A1 and hGCM1 to inhibit human trophoblast differentiation. Mol Cell Biol 33:1782-96
Chen, Chien-Cheng; Hardy, Daniel B; Mendelson, Carole R (2011) Progesterone receptor inhibits proliferation of human breast cancer cells via induction of MAPK phosphatase 1 (MKP-1/DUSP1). J Biol Chem 286:43091-102
Kumar, Premlata; Mendelson, Carole R (2011) Estrogen-related receptor gamma (ERRgamma) mediates oxygen-dependent induction of aromatase (CYP19) gene expression during human trophoblast differentiation. Mol Endocrinol 25:1513-26
Kumar, Premlata; Kamat, Amrita; Mendelson, Carole R (2009) Estrogen receptor alpha (ERalpha) mediates stimulatory effects of estrogen on aromatase (CYP19) gene expression in human placenta. Mol Endocrinol 23:784-93
Bukulmez, Orhan; Hardy, Daniel B; Carr, Bruce R et al. (2008) Androstenedione up-regulation of endometrial aromatase expression via local conversion to estrogen: potential relevance to the pathogenesis of endometriosis. J Clin Endocrinol Metab 93:3471-7

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