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Britta Jacobsen, Assistant Professor

Ph.D. (1999) Indiana University

 

Department of Medicine
Division of Endocrinology

Campus Box 8106
RC1-South, P18-7115
Phone: 303-724-3942

Britta.Jacobsen@ucdenver.edu

The two progesterone receptor (PR) isoforms, PR-B and the N-terminally truncated PR-A, are co-expressed in normal human tissues. PR-B and PR-A differentially regulate some target genes in human breast cancer cells. Although the two PR isoforms are expressed in equimolar amounts in normal tissues, some breast cancers express only PR-A or PR-B, or express an altered ratio of PR-A to PR-B. What are the effects of altering the PR ratio on breast cancer biology? Are there effects of progesterone receptors on gene expression in the absence of progesterone in human breast cancer cells? To address these questions, we have created cells that inducibly express PR. Starting with PR negative T47D-Y breast cancer cells, four cell lines were created: 1) inducible PR-A (Y iA), 2) inducible PR-B (Y iB), 3) stable PR-A with inducible PR-B (A iB), and 4) stable PR-B with inducible PR-A (B iA). I have used RNA from the Y iA and Y iB cells in gene chip experiments to identify genes that are regulated by PR in the absence of progesterone. I would like to determine the mechanism underlying the ability of PR regulate target genes in the absence or presence of progesterone by examining the promoter regions of these genes to identify common motifs and regions through which PR regulates gene expression. Because PR-A and PR-B differentially regulate subsets of genes in response to progesterone, I am also interested in the role of the PR ratio in regulating target genes and how altering the PR ratio affects breast cancer cell biology. We are also interested in how PR influence apoptosis. The Taxanes, paclitaxel (Px) and docetaxel (Dx), are among the most effective treatments for advanced breast cancers. Surprisingly little is known about the mechanism of Px and Dx induced apoptosis. While both Taxanes block cell proliferation, clinical studies suggest Dx is more effective than Px in inducing apoptosis. In addition, Dx is effective in Px resistant cancers. However, nothing is known about: 1) the mechanisms underlying differences in response to Dx. vs. Px; and 2) gene regulation by Taxanes in breast cancer. Also, while it is clear that Taxanes are effective for advanced disease, it is unclear whether response to Taxanes is influenced by presence of estrogen receptors (ER) or progesterone receptors (PR) in tumors. Some studies indicate that Taxanes are less effective in ER+ than ER- breast cancers. Others indicate that steroid receptors do not affect response to Taxanes. Thus the relationship between taxane sensitivity and ER/PR expression remains controversial. I have shown that ER+ breast cancer cells containing PR are more resistant to Px induced apoptosis than cells that lack PR. The mechanisms of Taxane induced apoptosis are unknown, as is influence of ER and PR on Taxane sensitivity of breast cancers. We are testing the hypotheses that Taxanes regulate gene expression in ER+ breast cancers, and Taxane induced apoptosis is desensitized by PR.


Jacobsen BM, Horwitz KB. Progesterone receptors, their isoforms and progesterone regulated transcription.  Mol Cell Endocrinol. 2011 Sep 17.  [Epub ahead of print].  PMID: 21952082

Badtke MM, Jambal P, Dye WW, Spillman MA, Post MD, Horwitz KB, Jacobsen BM. Unliganded progesterone receptors attenuate taxane-induced breast cancer cell death by modulating the spindle assembly checkpoint. Breast Cancer Res Treat. 2011 Feb 22.  [Epub ahead of print].  PMID: 21340479

Spillman MA, Manning NG, Dye WW, Sartorius CA, Post MD, Harrell JC, Jacobsen BM, Horwitz KB. Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis.  Cancer Res. 2010 Nov 1;70(21):8927-36.  Epub 2010 Oct 19.  PMID: 20959477

Pinto MP, Badtke MM, Dudevoir ML, Harrell JC, Jacobsen BM, Horwitz KB.  Vascular endothelial growth factor secreted by activated stroma enhances angiogenesis and hormone-independent growth of estrogen receptor-positive breast cancer.  Cancer Res. 2010 Apr 1;70(7):2655-64.  Epub 2010 Mar 23. PMID: 20332242

Jacobsen BM, Jambal P, Schittone SA, Horwitz KB.  ALU repeats in promoters are position-dependent co-response elements (coRE) that enhance or repress transcription by dimeric and monomeric progesterone receptors. Mol Endocrinol. 2009 Jul;23(7):989-1000.  Epub 2009 Apr 16. PMID: 19372234

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. PMID: 18637487

Jacobsen BM, Harrell JC, Jedlicka P, Borges VF, Varella-Garcia M, Horwitz KB (2006). Spontaneous fusion with, and transformation of mouse stroma by, malignant human breast cancer epithelium. Cancer Res. Aug 15;66(16):8274-9.

Ghatge RP, Jacobsen BM, Schittone SA, and Horwitz KB (2005) Medroxyprogesterone Acetate: A Dual Function Hormone that at Physiologic doses is both a Progestin and Androgen in Human Breast Cancer Cells.  Breast Cancer Research 7(6): R1036-R1050.

Jacobsen BM, Schittone SA, Richer JK, and Horwitz KB (2005) Progesterone Independent Effects of Human Progesterone Receptors (PR) in Estrogen Receptor Positive Breast Cancer: PR isoform-specific Gene Regulation and Tumor Biology.  Mol Endocinology 19(3):574-587.

Jacobsen BM, Richer JK, Sartorius CA, and Horwitz KB (2003) Expression Profiling of Human Breast Cancers and Gene Regulation by Progesterone Receptors.  J Mammary Gland Biol and Neoplasia 8(3):257-268.

Takimoto GS, Tung L, Abdel-Hafiz H, Abel MG, Sartorius CA, Richer JK, Jacobsen BM, Bain DL, and Horwitz KB. (2003) Functional Properties of the N-terminal Region of Progesterone Receptors and Their Mechanistic Relationship to Structure.  J Steroid Biochem Mol Biol. 85(2-5): 209-19.

Jacobsen BM, Richer JK, Schittone SA, and Horwitz KB. (2002) New Human Breast Cancer Cells to Study Progesterone Receptors (PR) Isoform Ratio Effects and Ligand-Independent Gene Regulation.  J. Biol Chem. 277(2): 27793-27800.


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