title: Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode.
abstract: BACKGROUND
  Somatostatin (SST) and cortistatin (CORT), two structurally and functionally related peptides, share a family of widespread receptors (sst1-5) to exert apparently similar biological actions, including endocrine/metabolic regulation and suppression of tumor cell proliferation. However, despite their therapeutic potential, attempts to apply SST-analogs to treat breast cancer have yielded unsatisfactory results. Actually, the specific roles of SST and CORT in mammary gland tumorigenesis (MGT), particularly in relation to metabolic dysregulation (i.e. obesity), remain unknown.
  
  
  METHODS
  The role of endogenous SST and CORT in carcinogen-induced MGT was investigated under normal (lean) and obesity conditions. To that end, SST- and CORT-knockout (KO) mice and their respective littermate-controls, fed low-fat (LF) or high-fat (HF) diets, were treated with 7,12-dimethyl-benza-anthracene (DMBA) once a week (wk) for 3 wk, and MGT was monitored for 25 wk. Additionally, we examined the effect of SST or CORT removal in the development of the mammary gland.
  
  
  RESULTS
  Lack of SST did not alter DMBA-induced MGT incidence under lean conditions; conversely, lack of endogenous CORT severely aggravated DMBA-induced MGT in LF-fed mice. These differences were not attributable to altered mammary gland development. HF-diet modestly increased the sensitivity to DMBA-induced carcinogenesis in control mice, whereas, as observed in LF-fed CORT-KO, HF-fed CORT-KO mice exhibited aggravated tumor incidence, discarding a major influence of obesity on these CORT actions. In marked contrast, HF-fed SST-KO mice exhibited much higher tumor incidence than LF-fed SST-KO mice, which could be associated with higher mammary complexity.
  
  
  CONCLUSIONS
  Endogenous SST and CORT distinctly impact on DMBA-induced MGT, in a manner that is strongly dependent on the metabolic/endocrine milieu (lean vs. obese status). Importantly, CORT, rather than SST, could represent a major inhibitor of MGT under normal/lean-conditions, whereas both neuropeptides would similarly influence MGT under obesity conditions. The mechanisms mediating these different effects likely involve mammary development and hormones, but the precise underlying factors are still to be fully elucidated. However, our findings comprise suggestive evidence that CORT-like molecules, rather than classic SST-analogs, may help to identify novel tools for the medical treatment of breast cancer.
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. raul.luque@uco.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. raul.luque@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. raul.luque@uco.es.|University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. raul.luque@uco.es.
authors.forename: Raúl M
authors.initials: RM
authors.lastname: Luque
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. b42viosa@uco.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. b42viosa@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. b42viosa@uco.es.|University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. b42viosa@uco.es.
authors.forename: Alicia
authors.initials: A
authors.lastname: Villa-Osaba
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. bc2lolof@uco.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. bc2lolof@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. bc2lolof@uco.es.|University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. bc2lolof@uco.es.
authors.forename: Fernando
authors.initials: F
authors.lastname: L-López
authors.affiliation: University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. anabel.pozo@hotmail.com.
authors.forename: Ana I
authors.initials: AI
authors.lastname: Pozo-Salas
authors.affiliation: Anatomical Pathology Service, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. patologiahrs@gmail.com.
authors.forename: Rafael
authors.initials: R
authors.lastname: Sánchez-Sánchez
authors.affiliation: Anatomical Pathology Service, Reina Sofia University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. rosam.ortega.sspa@juntadeandalucia.es.
authors.forename: Rosa
authors.initials: R
authors.lastname: Ortega-Salas
authors.affiliation: Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Palo Alto, CA, USA. llecea@stanford.edu.
authors.forename: Luis
authors.initials: L
authors.lastname: de Lecea
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. marinaalvarezbenito@telefonica.net.|Mammary Gland Unit, Reina Sofía University Hospital, University of Córdoba, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. marinaalvarezbenito@telefonica.net.
authors.forename: Marina
authors.initials: M
authors.lastname: Álvarez-Benito
authors.affiliation: CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. md1lomij@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. md1lomij@uco.es.|Lipids and Atherosclerosis Unit, Department of Medicine, Reina Sofía University Hospital, University of Córdoba, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. md1lomij@uco.es.
authors.forename: José
authors.initials: J
authors.lastname: López-Miranda
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. bc2gaorm@uco.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. bc2gaorm@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. bc2gaorm@uco.es.|University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. bc2gaorm@uco.es.
authors.forename: Manuel D
authors.initials: MD
authors.lastname: Gahete
authors.affiliation: Department of Cell Biology, Physiology, and Immunology, University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. justo@uco.es.|CIBER Fisiopatología de la Obesidad y Nutrición (CIBERobn), Córdoba, Spain. justo@uco.es.|Campus de Excelencia Internacional Agroalimentario, Córdoba, Spain. justo@uco.es.|University of Córdoba, Reina Sofía University Hospital, Maimonides Biomedical Research Institute of Córdoba (IMIBIC), Córdoba, Spain. justo@uco.es.
authors.forename: Justo P
authors.initials: JP
authors.lastname: Castaño
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics*; D005260:Female; D006801:Humans; D008321:Mammary Glands, Animal / Q000187:drug effects / Q000473:pathology; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008820:Mice, Obese / Q000235:genetics; D009479:Neuropeptides / Q000235:genetics*; D013004:Somatostatin / Q000235:genetics*
chemical_list: D009479:Neuropeptides; C099323:cortistatin; D013004:Somatostatin; D015127:9,10-Dimethyl-1,2-benzanthracene