Molecular effects of GH overexpression over breast tissue

BOJORGE MA; DIAZ ME; PIAZZA VG ; MIQUET JG ; SOTELO AI ; BARTKE A; GONZÁLEZ L

Buenos Aires

Congreso; Reunión Conjunta de Sociedades de Biociencias; 2017

Sociedad Argentina de Investigación Clínica

Breast cancer is a complex and heterogeneous pathology; therefore, approved therapies for its treatment often result in ineffectiveness or resistance. This highlights the importance of identifying new therapeutic targets and understanding the molecular mechanisms involved in their tumorogenic action. Lately, GH and IGF-I receptors have been associated with mammary tumorogenesis and their inhibitors proposed as plausible therapeutic agents. Thus, it is necessary to know in detail the molecular actions of these hormones in breast tissue. In order to achieve this aim, breast tissue from young adult transgenic mice overexpressing GH (PEPCK-bGH) and their non-transgenic siblings, considered as controls, were studied. The activation and expression of several receptors and signaling mediators that have been implicated in mammary carcinogenesis wereevaluated by Western blotting and RT-qPCR assays. The results showed that the expression of IGF-IR, EGFR and ERα, involved in normal development but also in malignant transformation of the mammary tissue, was increased in transgenic mice. The expression and activation of signaling molecules involved in cell proliferation and survival such as Erk1/2 and Src were similar and Akt activation was lower in mice overexpressing GH. In contrast, the activationof p38 was increased in transgenic animals. Finally, the expressionof different proto-oncogenes involved in cell cycle progression was determined. The protein levels of c-fos were higher in PEPCK-bGH mice. These findings suggest that elevated GH levels induce up-regulation of pro-mitogenic receptors and hyperactivation of the stress responding kinase p38, which might mediate transforming and pro-tumorogenic process over epithelial cells. In this manner, the results obtained contribute to a better understanding of signaling pathwaysinvolved in GH promotion of breast cancer.