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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA026869-33
Application #
8210884
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Sathyamoorthy, Neeraja
Project Start
1979-12-01
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
33
Fiscal Year
2012
Total Cost
$366,210
Indirect Cost
$123,710
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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
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
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
Kabos, Peter; Haughian, James M; Wang, Xinshuo et al. (2011) Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers. Breast Cancer Res Treat 128:45-55
Pinto, Mauricio P; Badtke, Melanie M; Dudevoir, Michelle L et al. (2010) Vascular endothelial growth factor secreted by activated stroma enhances angiogenesis and hormone-independent growth of estrogen receptor-positive breast cancer. Cancer Res 70:2655-64
Spillman, Monique A; Manning, Nicole G; Dye, Wendy W et al. (2010) Tissue-specific pathways for estrogen regulation of ovarian cancer growth and metastasis. Cancer Res 70:8927-36
Abdel-Hafiz, Hany; Dudevoir, Michelle L; Horwitz, Kathryn B (2009) Mechanisms underlying the control of progesterone receptor transcriptional activity by SUMOylation. J Biol Chem 284:9099-108

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