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Monique A. Spillman, Assistant Professor

MD, PhD (1999) University of Texas Southwestern Medical School


MoniqueSpillmanReproductiveSciences 

Department of Obstetrics & Gynecology

Section of Gynecologic Oncology

AO1 Room 4411

Phone: (303) 724

Fax:    (303) 724 3512

Monique.Spillman@ucdenver.edu

   

Modulation of Estrogen Response in a Mouse Xenograft Model of Steroid Hormone Sensitive Ovarian Cancer

Women are exposed to estrogen, the female steroid hormone, throughout their reproductive lives. As natural levels of estrogen fall in menopause, some women have taken hormone replacement therapy containing estrogen. When estrogen alone is taken in the menopause, it appears to increase the risk of developing ovarian cancer. 

Estrogen acts through the estrogen receptor (ER). At least 60% of ovarian cancers express the estrogen receptor, but it appears to act differently in ovarian cancers than in breast cancers. My research project is designed to identify estrogen regulated genes in ovarian cancers that may differ from those in breast cancers. We are also investigating drugs that inhibit estrogen receptor action in breast cancer, such as tamoxifen and letrozole in ovarian cancers.

Extended use of estrogen is difficult to mimic in short term cell culture models. For this reason, I have developed a unique ovarian cancer mouse model which allows rigorous, long-term, control of the steroid hormone (estrogen) microenvironment. When ER+ ovarian cancer cells are introduced into the model, they grow significantly. ER- cells in the same model demonstrate some growth, but lag behind the ER+ cells.

Women with advanced ovarian cancer are initially treated with a combination of surgery, followed by chemotherapy. Several maintenance chemotherapies have been tried to decrease the risk of recurrence; however, antiestrogen or aromatase inhibitor therapy has not been tried in this setting as a secondary preventative agent. We will use the mouse model to test the antiestrogen tamoxifen and aromatase inhibitor letrozole for effectiveness in inhibiting growth of ovarian tumors. In addition, we will examine ovarian tumors treated with estrogen, tamoxifen and letrozole to identify different patterns of gene expression.

Development of the mouse model has placed my research in a unique position to define the role of estrogen in the development and recurrence of ovarian cancer. The goal of this project is to identify new drug targets from the sets of estrogen regulated genes identified in our model system. In addition, our research may define a subset of women with ovarian cancer who may benefit from the addition of a hormonal agent to the standard chemotherapy.

Lange CA, Sartorius CA, Abdel-Hafiz H, Spillman MA, Horwitz KB, Jacobsen BM.
Progesterone receptor action: translating studies in breast cancer models to
clinical insights. Adv Exp Med Biol. 2008;630:94-111. Review. PubMed PMID:
18637487.

Spillman MA, Lacy J, Murphy SK, Whitaker RS, Grace L, Teaberry V, Marks JR,
Berchuck A. Regulation of the metastasis suppressor gene MKK4 in ovarian cancer.
Gynecol Oncol. 2007 May;105(2):312-20. Epub 2007 Feb 5. PubMed PMID: 17276500;
PubMed Central PMCID: PMC2796629.

Murphy SK, Huang Z, Wen Y, Spillman MA, Whitaker RS, Simel LR, Nichols TD,
Marks JR, Berchuck A. Frequent IGF2/H19 domain epigenetic alterations and
elevated IGF2 expression in epithelial ovarian cancer. Mol Cancer Res. 2006
Apr;4(4):283-92. PubMed PMID: 16603642.

Spillman MA, Schildkraut JM, Halabi S, Moorman P, Calingaert B, Bentley RC,
Marks JR, Murphy S, Berchuck A. Transforming growth factor beta receptor I
polyalanine repeat polymorphism does not increase ovarian cancer risk. Gynecol
Oncol. 2005 May;97(2):543-9. PubMed PMID: 15863158.

Taub S, Morin K, Sade RM, Spillman MA; Council on Ethical and Judicial Affairs
of the American Medical Association. Safeguards in the use of DNA databanks in
genomic research. Genet Med. 2004 Nov-Dec;6(6):526-9. PubMed PMID: 15545750.

Thai TH, Du F, Tsan JT, Jin Y, Phung A, Spillman MA, Massa HF, Muller CY,
Ashfaq R, Mathis JM, Miller DS, Trask BJ, Baer R, Bowcock AM. Mutations in the
BRCA1-associated RING domain (BARD1) gene in primary breast, ovarian and uterine
cancers. Hum Mol Genet. 1998 Feb;7(2):195-202. PubMed PMID: 9425226.

Spillman MA, Bowcock AM. BRCA1 and BRCA2 mRNA levels are coordinately elevated
in human breast cancer cells in response to estrogen. Oncogene. 1996 Oct
17;13(8):1639-45. PubMed PMID: 8895509.

Latest Publication in PubMed