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.
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.
|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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