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Kathryn B. Horwitz, Distinguished Professor

Ph.D. (1975) University of Texas Southwestern Medical School



Department of Medicine
Division of Endocrinology
Campus Box 8106
RC1-South, L18-7402-D

Phone: 303-724-3921

Kate.Horwitz@ucdenver.edu

Research in our laboratory focuses on the actions of women's ovarian hormones, estradiol and progesterone, and their role in breast cancer. These hormones activate intranuclear receptors that regulate gene transcription. In breast cancers, estrogen (ER) and progesterone (PR) receptors control tumor development and growth, they are markers of hormone dependence and tumor aggressiveness, and they are targets for treatments with antiestrogens, aromatase inhibitors and progestins. The lab consists of approximately 15 collaborating investigators with appointments as junior faculty, postdoctoral and clinical fellows, graduate and medical students, and research assistants. The research in breast cancer ranges from basic molecular biology of receptor action in transcription, to cell and tumor biology, role of hormones in metastasis, and translational studies.

Nuclear Receptors and Transcription. 1. To understand why two forms of PR - the PR-A and PR-B isoforms - have different transcriptional activites and different roles in breast cancer prognosis, tumor growth, and response to treatments, we have undertaken detailed protein structural analyses of the two receptors focused on the large N-terminal region. To this end the proteins are overexpressed in insect cells, purified to homogeneity, and analyzed by a variety of protein structural and biophysical methods. 2. Studies also include detailed N-terminal mapping studies involving site-specific and random mutagenesis of regions unique to PR-B, and studies addressing the role of post-transcriptional protein modifications, like phosphorylation and SUMOylation, on receptor function. 3. N-terminal binding, transcriptional coregulatory proteins are being identified.

Cell Biology. 4. We take advantage of the power of expression profiling to define genes involved in estrogen and progesterone signaling, cross-talk between the two receptor systems, tumor metastasis, etc. 5. Inducible human breast cancer cell models have been developed in which receptors are "off" until switched "on. These are used to refine expression analyses, to probe for ligand-independent effects of receptors, and to analyze differential receptor effects on tumor response to hormonal and chemotherapeutic agents including effects of taxanes.

Tumor Biology. 6. Hormones and breast cancer growth. Different human breast cancer cell lines with varying ER and/or PR content are grown as hormone dependent tumors in nude mice and analyzed for the role of receptors, hormones and hormonal treatments, on tumor growth and regression. 7. Breast cancer metastasis. Powerful new models have been created using highly green and red fluorescent tumor cells that allow accurate tracking of the spread of cells out of primary tumor sites to metastatic sites in the nude mice. Expression profiling and other studies address mechanisms for hormone regulation of metastases.

Translational. 8. In collaborative studies, the observations and hypotheses derived from basic research studies are extended into translational research using tumors taken from patients. 9. Patient tumor samples are also used to analyze the role of tumor cells in altering the tumor microenvironment and stromal/epithelial cell interactions.

Takimoto GS, Tung L, Abdel-Hafiz H, Abel MG, Sartorius CA, Richer JK, Jacobsen BM, Bain DL and Horwitz KB. Functional properties of the N-terminal region of progesterone receptors and their mechanistic relationship to structure. J STER BIOCH & MOL BIOL, 85: 209-219, 2003.

Jacobsen BM, Richer JK, Sartorius CA and Horwitz KB. Expression profiling of human breast cancers and gene regulation by progesterone receptors. J OF MAMMARY GLAND BIOLOGY & NEOPLASIA, 8:257:268, 2003.

Hopp TA, Weiss HL, Hilsenbeck SG, Cui Y, Allred DC, Horwitz KB and Fuqua SAW. Breast cancer patients with Progesterone Receptor-A rich tumors have poorer disease-free survival. CLINICAL CANCER RESEARCH, 10:2751-2760, 2004.

Jacobsen BM, Richer JK, Schittone S and Horwitz KB. Progesterone independent effects of progesterone receptors (PR) in estrogen receptor positive breast cancer: PR isoform-specific gene regulation and tumor biology. MOLECULAR ENDOCRINOLOGY, 19(3): 574-587, 2005.

Fuqua SAW, Cui Y, Lee AV, Osborne CK and Horwitz KB. Response to: "Time to Stop Progesterone Receptor Testing in Breast Cancer Management. Olivoto et al. JCO 22(2004):1769". JOURNAL OF CLINICAL ONCOLOGY, 23(4): 931-932, 2005.

Chadli A, Graham JD, Abel MG, Jackson TA, Gordon DF, Wood WM, Felts SJ, Horwitz KB and Toft DO. GC UNC-45 is a novel co-chaperone for the progesterone receptor/hsp 90 pathway. EMBO J, in press, 2005.

Ghatge R, Jacobsen BM, Schittone S, Horwitz KB. Medroxyprogesterone acetate in breast cancer cells: Gene regulatory overlap with dihydrotestosterone in breast cancer cells. ENDOCRINOLOGY, in press 2005.

Sartorius CA, Harvell DME, Shen T and Horwitz KB. Progestins initiate a luminal to myoepithelial switch in estrogen dependent human breast tumors without altering growth. CANCER RESEARCH, in press 2005.

Harvell DME, Sartorius CA, Richer JK, Allred DC and Horwitz KB. Estrogens regulate different genes in human breast tumor xenorafts compared to the identical cells in culture. Submitted, 2005.

Latest Publications in PubMed