This renewal continues research on estrogens (E) and progestins (P) in luminal, estrogen (ER) and progesterone (PR) receptor-positive human breast cancer. In the preceding cycle 27 papers were published. Relevant to this renewal, we: 1. Developed fluorescent mouse models of ER+PR+ tumors that metastasize to lymph nodes (LN). Compared to primary tumors, LN metastases are E resistant. 2. Demonstrated that ER+PR+ tumors contain a minor ER-PR- subpopulation that expresses cytokeratin 5 (CK5). These rare cells may be tumor-initiating and are expanded by P. 3. Initial ER+PR+ models of distant metastasis show hormonal influences on organ-specific engraftment. Metastatic breast cancer kills more than 40,000 American women each year and two-thirds of these tumors retain ER or PR. Despite clinical evidence that ER+PR+ tumors metastasize, the role of women's steroid hormones or their receptors on metastases is unknown, due to lack of models. Hypotheses: 1. E and P play critical roles on LN and distant metastasis of ER+PR+ disease. 2. In ER+PR+ disease, an ER-PR-CK5+ subpopulation with tumor-initiator properties is expanded by P and influences metastasis, dormancy and drug resistance. 3. Luminal ER+PR+ breast cancers exhibit receptor plasticity characterized by receptor loss, in a process driven by P.
AIM 1. Metastasis Models of ER+PR+, hormone dependent breast cancer and role of estrogens. To develop models of ER+PR+ metastasis starting from solid tumors or circulating tumor cells, and test the hypothesis that E and P play a role in metastatic engraftment of ER+PR+ disease.
AIM 2. Tumor-initiating cells in ER+PR+ breast cancer, tumor dormancy and drug resistance. To test the hypothesis that ER+PR+CK5- breast cancers harbor rare pre-existing ER-PR-CK5+ cells with tumor-initiating properties. ER-PR-CK5+ cells are expanded by P. We engineer models to study constitutive and P-regulated live ER-PR-CK5+ tumor cells and their role in recurrent disease.
AIM 3. Towards a new biology for progesterone in luminal breast cancer. To explore a novel view of P in ER+PR+ breast cancers focused on P regulation of tumor-cell phenotype. We test the hypothesis that luminal breast cancers exposed t exhibit receptor plasticity associated with receptor loss. We study cell- biological and molecular mechanisms of this plasticity, develop methods to distinguish among putative ER-PR- cell subtypes, determine whether or not they represent a continuum of the same cells, and study CK5 regulation by P. In sum, the majority of breast cancer metastases are ER+PR+, so E and P must play critical roles in this process. E is the proliferative hormone. P is not. Rather, P partially extinguishes receptor expression. Receptor loss in a subset of ER+PR+ tumor cells is dangerous because these cells acquire tumor-initiating properties that secondarily promote tumor expansion. This has consequences on metastasis and disease recurrence.

Public Health Relevance

The majority of breast cancers are luminal estrogen (ER) and progesterone (PR) receptor-positive, so estrogens (E) and progestins (P) must play critical roles in this disease subtype. The proliferative role of E is established. The role of P is unclear. We suggest that P influence the phenotype of luminal cancers and target the plasticity of this disease by partially extinguishing receptor expression. Receptor loss in a subset of cells is dangerous because these cells have tumor- initiating properties that secondarily promote tumor expansion and drug resistance. This has consequences for metastasis and tumor recurrence.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Colorado Denver
Internal Medicine/Medicine
Schools of Medicine
United States
Zip Code
Abdel-Hafiz, Hany A; Dudevoir, Michelle L; Perez, Daniel et al. (2018) SUMOylation Regulates Transcription by the Progesterone Receptor A Isoform in a Target Gene Selective Manner. Diseases 6:
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2015) Role of epigenetic modifications in luminal breast cancer. Epigenomics 7:847-62
Ogba, Ndiya; Manning, Nicole G; Bliesner, Brian S et al. (2014) Luminal breast cancer metastases and tumor arousal from dormancy are promoted by direct actions of estradiol and progesterone on the malignant cells. Breast Cancer Res 16:489
Pinto, Mauricio P; Dye, Wendy W; Jacobsen, Britta M et al. (2014) Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. BMC Cancer 14:735
Knox, Aaron J; Scaling, Allison L; Pinto, Mauricio P et al. (2014) Modeling luminal breast cancer heterogeneity: combination therapy to suppress a hormone receptor-negative, cytokeratin 5-positive subpopulation in luminal disease. Breast Cancer Res 16:418
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2014) Post-translational modifications of the progesterone receptors. J Steroid Biochem Mol Biol 140:80-9
Jambal, Purevsuren; Badtke, Melanie M; Harrell, J Chuck et al. (2013) Estrogen switches pure mucinous breast cancer to invasive lobular carcinoma with mucinous features. Breast Cancer Res Treat 137:431-48
Harvell, Djuana M E; Kim, Jihye; O'Brien, Jenean et al. (2013) Genomic signatures of pregnancy-associated breast cancer epithelia and stroma and their regulation by estrogens and progesterone. Horm Cancer 4:140-53
Haughian, James M; Pinto, Mauricio P; Harrell, J Chuck et al. (2012) Maintenance of hormone responsiveness in luminal breast cancers by suppression of Notch. Proc Natl Acad Sci U S A 109:2742-7
Abdel-Hafiz, Hany A; Horwitz, Kathryn B (2012) Control of progesterone receptor transcriptional synergy by SUMOylation and deSUMOylation. BMC Mol Biol 13:10

Showing the most recent 10 out of 88 publications