RC1 South L18-5403
Office phone: 303-724-3937
Lab phone: 303-724-4323
The most common breast cancer type is called luminal and contains receptors for the female steroid hormones estradiol and progesterone (ER and PR). Luminal breast cancers are normally treated with endocrine therapies attacking the hormone signaling axis. However, recurrent drug resistant luminal tumors, that often appear >5 years post initial treatment, account for the majority of mortality from breast cancer. Our laboratory seeks to determine mechanisms unique to luminal breast cancer that allow for this adverse progression. We originally identified that progesterone regulates the number of cancer stem/progenitor cells, thought to underlie cancer resistance and recurrence, within luminal breast cancers. Further studies are investigating how estradiol and progesterone through ER and PR regulate cancer cell stemness, particularly by controlling the expression of lineage determinant genes, and seek to identify novel therapeutic targets specific to luminal breast cancer stem cells. We utilize a number of historic and novel breast cancer cell lines labeled with trackable fluors to pursue these studies. In collaboration with the laboratory of Peter Kabos in the Medical Oncology Division, we have developed transplantable patient-derived xenografts from a variety of human primary and metastatic breast cancers. These breast tumor explants represent a variety of clinical subtypes, including both luminal and “triple negative” cases, and serve as unique models to explore hormonal regulation of stem cells, and novel stem-cell targeted therapeutics.
Current lab projects:
1. Regulation of breast cancer stem cells by progesterone and PR. Progesterone increases the number of cells with a cancer stem cell phenotype measured by expression of the tumor initiating cell marker CD44 and progenitor cell marker cytokeratin 5 (CK5). We have engineered optical reporter models to track and isolate cells based on expression of stem cell markers. As such we can isolate “stem-like” and “non stem-like” breast cancer cells and measure properties such as drug resistance, self-renewal, and tumor initiation, under different hormone and treatment conditions. Our goal is to assess if transient or sustained hormone exposure reprograms breast cancer cells into cancer stem cell phenotype, determine the molecular mechanisms dictating this, and whether this is a reversible phenotype.
2. PR gene regulation in diverse patient-derived breast cancer xenografts. Progestins (natural and synthetic derivatives) influence the incidence of breast cancer particularly in relation to hormone replacement therapy. However, little is known of progestin mechanism of action in whole human tumor models. In addition, progestins are pro-tumorigenic in some cases and are potently anti-estrogenic in others. We seek to understand the divergent actions of progestins by using patient-derived breast cancer xenografts that are PR+, and treated with or without progestins, to assay global changes in gene expression. Our goal is to create a roadmap of progestin action in a variety of tumors, aligned with progestin-dependent tumor growth trends, to better predict the therapeutic potential of hormone and antihormones.
3. Small molecules that reverse the cancer stem cell phenotype in luminal breast cancers. We are working with the LaBarbera laboratory in the Department of Pharmaceutical Sciences to identify small molecule inhibitors of the cancer stem cell phenotype in luminal breast cancers. Using reportable constructs we have initially identified several natural compounds that inhibit the progestin-induced cancer stem cell phenotype. We are expanding these studies to identify additional compounds that block the cancer stem cell phenotype, and thus may be effective in combinatorial therapies at preventing luminal breast cancer recurrences.
Purvi Patel, M.S. (Cancer Biology graduate student)
Jessica Finlay-Schultz, Ph.D. (post-doctoral fellow)
Diana Cittelly, Ph.D. (senior post-doctoral fellow)
Select recent publications:
1. 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 Natl Acad Sci USA, 105(15): 5774-9, 2008. PMID:18391223
2. Horwitz KB and Sartorius CA. 2008. Progestins in hormone replacement therapies reactivate cancer stem cells in women with pre-existing breast cancers: a hypothesis. J Clin Endocrinol Metab, 93(9): 3295-8, 2008. PMID:18647813
3. Cittelly D, Richer JK, and Sartorius CA. Ovarian steroid hormones: what’s hot in the stem cell pool? Breast Cancer Res, 2010;12(4):309. PMID:20825628.
4. Kabos P, Haughian JM, Wang X, Dye WW, Elias A, Horwitz KB, and Sartorius CA. Cytokeratin 5 positive cells represent a drug resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat, 2011; [Epub 7/29/2010] 128(1):45-55. PMID:20665103.
5. Axlund D and Sartorius CA. Progesterone Regulation of Stem Cells in Normal and Malignant Breast. Mol Cell Endocrinol, 2012; 357(1-2): 71-79. PMID:21945473
6. Yoo BH, Axlund SD, Kabos P, Reid BG, Schaack J, Sartorius CA and LaBarbera DV. A high content assay to identify small molecule modulators of a cancer stem cell population in luminal breast cancer. J Mol Screening, 2012 Jun 29 [Epub ahead of print] PMID:22751729
7. Cittelly DM, Finlay-Schultz J, Howe EN, Spoelstra N, Axlund SD, Hendricks P, Jacobsen BM, Sartorius CA and Richer JK. Progestin-mediated suppression of miR-29 potentiates de-dedifferentiation of breast cancer cells through upregulation of KLF4. Oncogene, 2012 Jul 2 [Epub ahead of print] PMID:22751119.
8. Kabos P, Finlay-Schultz J, Li C, Kline E, Finlayson C, Wisell J, Edgerton SM, Harrell JC, Elias A and Sartorius CA. Patient-derived luminal breast cancer xenografts retain hormone receptor heterogeneity and help define unique estrogen dependent gene signatures. Breast Cancer Res Treat, 2012 Sept;135(2):415-32. Epub 2012 Jul 24. PMID:22821401
9. Axlund SD, Yoo B, Kabos P, Rosen RB, Schaack J, LaBarbera D and Sartorius CA. Progesterone-inducible cytokeratin 5 positive cells in luminal breast cancer exhibit progenitor properties. Hormones and Cancer, 2013 Feb;4(1):36-49. PMID:23184698