Phone: (303) 724-3921
Kathryn Horwitz, PhD is a University of Colorado Distinguished Professor on the faculty of the Endocrinology division of the Department of Medicine. Her lab studies “luminal” breast cancers; the approximately 75% of all breast cancers whose growth is dependent on women’s hormones, and whose treatment include suppression of hormone signaling. The lab consists of ~15 faculty associates, basic and clinical postdoctoral fellows, graduate students and research assistants.
Recent published papers and work in progress deal with studies of the molecular biology of estrogen and progesterone receptors; analysis of the stem/progenitor cells of luminal breast cancers; modeling of hormone dependent breast cancer metastasis; translational studies contrasting the genomic underpinnings of hormone-responsive vs. hormone-resistant tumors in patients.
In June 2010 Kate received the Fred Conrad Koch Award; the highest honor bestowed by The Endocrine Society in recognition of exceptional contributions to endocrinology. In January 2011, Kate will receive the Rosalind E. Franklin Award of the National Cancer Institute, which recognizes the contributions made to cancer research by women.
Kate’s lab is supported by grants and fellowships from the Avon Foundation, the Breast Cancer Research Foundation, the National Foundation for Cancer Research, the National Cancer Institute of the NIH, the Komen Foundation and the Department of Defense. Her major NIH grant, which she has held continuously for 30 years, was renewed for another 5 years in December 2009.
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.
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.
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.
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.
Harrell JC, Dye WW, Sartorius CA and Horwitz KB. Contaminating cells alter gene signatures in whole organ versus laser capture microdissected tumors: A comparison of experimental breast cancers and their lymph node metastases. CLINICAL AND EXPERIMENTAL METASTASIS, 25:81-88, 2008
Harvell DME, Spoelstra NS, Singh M, Finlayson C, Phang T, Hunter L, Dye WW, Borges VB, Elias AD, Horwitz KB and Richer JK. Molecular signatures of neoadjuvant endocrine therapy for breast cancer: Characteristics of response or intrinsic resistance. BREAST CANCER RESEARCH & TREATMENT, 112: 475-488, 2008
Harvell DME, Richer JK, Singh M, Spoelstra N, Finlayson C, Borges VB, Elias AD and Horwitz KB. Estrogen regulated gene expression in response to neoadjuvant endocrine therapy of breast cancers: Tamoxifen agonist effects dominate in the presence of an aromatase inhibitor. BREAST CANCER RESEARCH & TREATMENT, 112: 489-501, 2008
Horwitz KB, Dye WW, Harrell JC, Kabos P and Sartorius CA. Rare steroid receptor negative basal-like tumorigenic cells in luminal subtype human breast cancer xenografts, PROC NAT ACAD SCI, 105(15): 5774-5779, 2008
Singh M, Spoelstra NS, Howe JA, Torkko KC, Clark HR, Darling DS, Shroyer KK, Horwitz KB, Broaddus RR and Richer JK. ZEB1 expression in Type I vs. Type II endometrial cancers: a marker of aggressive disease. MODERN PATHOLOGY, 21: 912-923, 2008.
Horwitz KB and Sartorius CA. COMMENTARY: Progestins in hormone replacement therapies reactivate cancer stem cells in occult breast cancers: a hypothesis. J CLIN ENDO & METAB, 93(9): 3295-3298, 2008
Horwitz KB. Update of estrogen plus progestin therapy for menopausal hormone replacement and an explanation for the associated increased risk of breast cancer. MOLEC ENDOCR, 22: 2743-2750, 2008
Abdel-Hafiz H, Dudevoir M, and Horwitz KB. Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation. J BIOL CHEM, 284(14): 9099-9108, 2009
Jacobsen BM, Jambal P, Schittone SA and Horwitz KB. ALU-like repeats in promoters are position dependent co-response elements (coRE) that enhance or repress transcription by dimeric and monomeric progesterone receptors. MOLECULAR ENDOCRINOLOGY, 23(7); 989-1000, 2009
Micalizzi DS, Christensen KL, Jedlicka P, Coletta RD, Baron AE, Harrell JC, Horwitz KB, Billheimer D, Heichman K, Welm A, Schiemann WP and Ford HL. The Six1 homeoprotein induces epithelial to mesenchymal transition and breast cancer metastasis via Transforming Growth Factor-, JOUR CLINICAL INVESTIGATION, 119(9): 2528-2531, 2009
Pinto MP, Badtke MM, Dudevoir ML, Harrell JC, Jacobsen BM and Horwitz KB. Vascular endothelial growth factor secreted by activated stroma enhances angiogenesis and hormone independent growth of estrogen receptor positive breast cancer. CANCER RESEARCH, 70 (7): 2655-2664, 2010.
Kabos P, Haughian JM, Wang X, Dye WW, Finlayson C, Elias A, Horwitz KB and Sartorius CA. Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant cell subpopulation in luminal breast cancers. BREAST CANCER RESEARCH AND TREATMENT, in press, 2010
Spillman MA, Sartorius CA, Harrell JC, Manning N, Jacobsen BM and Horwitz KB. Estrogen alters tumor growth and metastatic pattern in a human ovarian cancer nude mouse xenograft model. CANCER RESEARCH, 2010 in press