Meeting Report 26th Pezcoller Symposium: Cancers Driven by Hormones Myles Brown 1 , Arul Chinnaiyan 2 , Antonella Farsetti 3 , David M. Livingston 4 , Massimo Loda 5 , Roland Schuele 6 , and Enrico Mihich 1 Abstract This symposium was held in Trento, Italy, on June 19–21, 2014, and was focused on advances in biology, physiology, and pathol- ogy of neoplasms affected by hormones, especially breast and prostate cancers. The stem cell function, the genetic and epigenetic interactions with hormones, the mechanisms of estrogen receptor transcription, biochemical markers and therapeutic targets in breast cancer, promotion of breast cancer carcinogenesis by pro- gesterone, the basis for prostate cancer progression and the relevance of DNA repair processes, androgen receptor program- ming during prostate carcinogenesis, the metabolic stress role in tumor survival, and the diagnostic use of imaging in prostate cancer were discussed. Cancer Res; 75(7); 1177–80. Ó2015 AACR. Hans Clevers (Utrecht Institute, Utrecht, the Netherlands) gave the keynote address. He defined Lgr5 þve as a Wnt target gene that drives crypts stem cells in colon cancer. Lgr5 þve crypt base colum- nar cells generated all epithelial lineages throughout life. Lgr5 þve stem cells can initiate ever-expanding crypt–villus organoids in three-dimensional (3D) culture. Intestinal cancer is initiated by Wnt pathway–activating mutations in genes, such as APC. Deletion of APC identifies the stem cell as the cell-of-origin of adenomas. A stem cell/progenitor cell hierarchy is maintained in early stem cell–derived adenomas, lending support to the "cancer stem cell" concept. Lgr5 stem cell division occurs sym- metrically. Paneth cells are CD24 þ and express EGF, TGF-a, Wnt3, and the Notch ligand Dll4, all essential signals for stem-cell maintenance in culture. Coculturing of stem cells with Paneth cells improves organoid formation. Genetic removal of Paneth cells in vivo results in the concomitant loss of Lgr5 stem cells. Mechanisms of Tumor Cell Hormone Responsiveness Sohail Tovazoie (The Rockefeller University, New York, NY) indicated that small RNAs, ApoE, and LRP comprise a druggable antimetastatic melanoma network. Specific microRNA sets govern metastatic progression of breast cancer and melanoma. MiR- 199a-5p, miR-199a-3p, and miR-1908 are highly overexpressed in metastatic melanoma cells and are metastatic promoters and convergently target the secreted protein ApoE, which is a strong suppressor of melanoma invasion, endothelial recruitment, and metastatic colonization. ApoE is a secreted protein that mediates these effects through its engagement of the LRP1 receptor on melanoma cells and LRP8 receptor on endothelial cell. Transcrip- tional ApoE induction (through pharmacologic activation of the Liver-X nuclear hormone receptor) inhibits tumor growth, endo- thelial cell proliferation, and metastasis. Miguel Beato (Centre de Regulacio Genomica, Barcelona, Spain) discussed the structural dynamics in hormonal gene reg- ulation. Breast cancer cells respond to steroid hormones by extensive changes in 4,000 genes' expression. The T47D cell response to progestins showed that the organization in nucleo- somes of the DNA sequences recognized by the progesterone receptor (PR) is key for the initiation of chromatin remodeling response, which depends on PR-associated enzymatic activities. The genome division in consecutive topological association domains (TAD) contributes to coordination of hormonal responses. Repressed TADs compact in response to hormone and the interactions among their genes decrease, whereas activated TADs expand and the interactions among their genes increase. These findings underline the importance of the various chromatin structure levels for gene regulation and lead to the proposal that TADs behave as "regulons" in the cell response to external signals. Hormonal Signaling in Breast Cancer Myles Brown (Dana Farber Cancer Institute, Boston, MA) out- lined the genetic and epigenetic determinations of hormone dependence. Specific drugs targeting the enzymes responsible for steroid synthesis and the steroid receptors and the development of the estrogen receptor (ER) led to the first breast cancer predictive biomarker and the first molecularly defined therapeutic target. ER mutations can explain resistance to endocrine therapy in 20% of patients with advanced disease. These mutations activate the receptor in the absence of hormone and make it resistant to existing antagonists. They support the conclusion that the tumor-initiating cell is ER dependent. Mutations in other com- ponents of hormone signaling have not yet been validated as mechanisms of endocrine resistance. Genetic mechanisms of 1 Medical Oncology, Dana Farber Cancer Institute, Boston, Massachu- setts. 2 Howard Hughes Medical Institute, University of Michigan, Ann Arbor, Michigan. 3 Institute of Cell Biology and Neurobiology, National Research Council, Rome, Italy. 4 Cancer Biology, Dana Farber Cancer Institute, Boston, Massachusetts. 5 Center for Molecular Oncologic Pathology, Dana Farber Cancer Institute, Boston, Massachusetts. 6 Central Clinical Research, Freiburg University Medical Center, Frei- burg, Germany. Corresponding Author: Enrico Mihich, Dana Farber Cancer Institute, 450 Brook- line Avenue, Boston, MA 02115-5450. Phone: 716-316-7782; Fax: 617-582-8550; E-mail: enrico_mihich@dfci.harvard.edu doi: 10.1158/0008-5472.CAN-14-2902 Ó2015 American Association for Cancer Research. Cancer Research www.aacrjournals.org 1177 on October 14, 2021. © 2015 American Association for Cancer Research. cancerres.aacrjournals.org Downloaded from Published OnlineFirst March 18, 2015; DOI: 10.1158/0008-5472.CAN-14-2902