A soluble form of GAS1 inhibits tumor growth and angiogenesis in a triple negative breast cancer model

• Published in: Experimental cell research 2014-10, Vol.327 (2), p.307-317
• Main Authors: Jiménez, Adriana, López-Ornelas, Adolfo, Estudillo, Enrique, González-Mariscal, Lorenza, González, Rosa O., Segovia, José
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Apoptosis; Artemin; Blotting, Western; Breast cancer; Cell Cycle; Cell Cycle Proteins - genetics; Cell Cycle Proteins - metabolism; Cell growth; Cell Movement; Cell Proliferation; Culture Media, Conditioned - pharmacology; Endothelium, Vascular - cytology; Endothelium, Vascular - metabolism; ERK1/2; Female; Flow Cytometry; Fluorescent Antibody Technique; GPI-Linked Proteins - genetics; GPI-Linked Proteins - metabolism; Growth Arrest Specific 1; Humans; MAP Kinase Signaling System; Mice; Mice, Nude; Neovascularization, Pathologic - prevention & control; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Phosphorylation; Rats; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Signal transduction; tGAS1; Triple Negative Breast Neoplasms - blood supply; Triple Negative Breast Neoplasms - metabolism; Triple Negative Breast Neoplasms - pathology; Triple Negative Breast Neoplasms - prevention & control; Tumor Cells, Cultured; Xenograft Model Antitumor Assays
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2014.06.016

We previously demonstrated the capacity of GAS1 (Growth Arrest Specific 1) to inhibit the growth of gliomas by blocking the GDNF–RET signaling pathway. Here, we show that a soluble form of GAS1 (tGAS1), decreases the number of viable MDA MB 231 human breast cancer cells, acting in both autocrine and paracrine manners when secreted from producing cells. Moreover, tGAS1 inhibits the growth of tumors implanted in female nu/nu mice through a RET-independent mechanism which involves interfering with the Artemin (ARTN)-GFRα3-(GDNF Family Receptor alpha 3) mediated intracellular signaling and the activation of ERK. In addition, we observed that the presence of tGAS1 reduces the vascularization of implanted tumors, by preventing the migration of endothelial cells. The present results support a potential adjuvant role for tGAS1 in the treatment of breast cancer, by detaining tumor growth and inhibiting angiogenesis. •GAS1 is involved in cell cycle arrest.•tGAS1 is a soluble form of GAS1 with paracrine effect.•GAS1 and tGAS1 induce cell cycle arrest of MDA MB 231 human breast cancer cells.•tGAS1 inhibits the ARTN–GFRα3 interaction and ERK signaling.•tGAS1 decreases tumor growth and angiogenesis in immunocompromised mice.