Tissular and molecular effects on mammary gland of GH/IGF-I up-regulation

BOJORGE MA ; CICCONI N; CEBRÓN J ; SOTELO AI ; MIQUET JG ; GONZALEZ L

Buenos Aires

Congreso; ICE 2021 Virtual: 19th International Congress of Endocrinology, 4th Latin American Congress of Endocrinology and 13th Congress of the Argentine Federation of Endocrinology Societies; 2021

Introduction: Breast cancer is the most frequently occurring cancer in women and the second most common cancer in general, worldwide. There are various types of therapies for breast tumors but, regrettably, the heterogeneity and complexity of tumors often result in resistance and long-term ineffectiveness of those clinical approaches, which highlights the importance of identifying new therapeutic targets. Growth hormone (GH) and insulin growth factor-I (IGF-I) are essential for normal mammary growth and development. However, there is evidence, in animal models and humans, relating their upregulation with tumorigenic processes of the breast. Consequently, GH and IGF-I receptor have been suggested as possible therapeutic targets for the treatment of breast cancer. However, the pro-oncogenic effects of GH and IGF-I over mammary tissue at the tissular and molecular level have not been fully elucidated.Objectives: The aim of this work was to ascertain, at the tissular and molecular levels, how elevated concentrations of GH and IGF-I could promote or facilitate mammary tissue oncogenic Transformation.Methods: The mammary tissue from 15-week old transgenic virgin female mice overexpressing GH (GH-Tg) and their normal siblings were studied. Whole mounting, and hematoxylin and eosin staining of the gland were performed. Besides, expression of several receptors, signaling mediators and transcription factors linked with development, proliferation and survival as well as with oncogenic processes in breast tissue were evaluated by Western blotting and RT-qPCR.Results: Morphological and histological studies showed significantly less duct and alveolar structures, but major proportion of terminal ends buds (TEBs), in the mammary tissue from transgenic. The receptors of IGF-I, epithermal growth factor and estrogen were increased in the transgenic animals. Besides, GH and IGF-I mRNA levels were augmented in GH-Tg breast tissue as well as the expression of the proto-oncogene c-fos. However, the activation of Akt and Src were lower in GH-Tg compared to control animals, while the activation of p38 was increased.Conclusion: The upregulation of GH/IGF-I induces morphological alterations in the mammary gland and increased expression of receptors associated to mitogenic processes, which affect normal breast development. While these effects are non-tumorigenic per se, they might predispose to oncogenic transformation.