RT Journal Article
T1 Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode.
A1 Luque, Raul M
A1 Villa-Osaba, Alicia
A1 L-Lopez, Fernando
A1 Pozo-Salas, Ana I
A1 Sanchez-Sanchez, Rafael
A1 Ortega-Salas, Rosa
A1 de Lecea, Luis
A1 Alvarez-Benito, Marina
A1 Lopez-Miranda, Jose
A1 Gahete, Manuel D
A1 Castaño, Justo P
K1 Cortistatin
K1 Somatostatin
K1 Mammary gland
K1 Tumorigenesis
K1 Obesity
K1 Mouse models
AB 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. 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. 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. 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.
PB BioMed Central
YR 2016
FD 2016-03-08
LK http://hdl.handle.net/10668/9902
UL http://hdl.handle.net/10668/9902
LA en
NO Luque RM, Villa-Osaba A, L-López F, Pozo-Salas AI, Sánchez-Sánchez R, Ortega-Salas R, et al. Lack of cortistatin or somatostatin differentially influences DMBA-induced mammary gland tumorigenesis in mice in an obesity-dependent mode. Breast Cancer Res. 2016 Mar 8;18(1):29
NO This work has been supported by the following grants: BIO-0139, CTS-1406,PI-0639-2012 (funded by Junta de Andalucía), Proyectos de Investigación enSalud (FIS) PI13-00651 (funded by Instituto de Salud Carlos III), BFU2013-43282-R (funded by Ministerio de Economía y Competitividad) and CIBERobn (to RML and JPC). FPU12/01086 grant from Ministerio de Educación, Cultura y Deporte (to AVO), “Sara Borrell” program CD11/00276 (to MDG). CIBER is an initiative of Instituto de Salud Carlos III, Ministerio de Sanidad, Servicios Sociales e Igualdad, Spain. The authors gratefully acknowledge all the individuals who took part in these studies and all the researchers, clinicians, technicians, and administrative staff who enabled this work to be carried out.
DS RISalud
RD Apr 17, 2025