title: GDNF induces RET-SRC-HER2-dependent growth in trastuzumab-sensitive but SRC-independent growth in resistant breast tumor cells.
abstract: We investigated the role of glial cell line-derived neurotrophic factor (GDNF) in compensating trastuzumab (TZMB)-induced apoptosis in HER2+breast cancer (BC) cells using xenograft tumors. We generated BC xenografts in nude mice using samples from three patients selected based on their HER2 status and response to TZMB therapy. TZMB treatment resulted in shrinkage of the HER2+TZMB-sensitive xenograft tumor but not the HER2-or HER2+TZMB-resistant ones. GDNF neutralized TZMB activity and induced growth in all tumors. Three distinct cell lines were derived from these tumors and named, respectively, TZMB-sensitive (TSTC), HER2-(HNTC), and TZMB-resistant (TRTC). Over 50% of TRTC but 1% of TSTC cells expressed CD44, whereas 84% of TSTC were CD24+compared to only 1% of TRTC, despite comparable levels of HER2 detected in both. TZMB induced profound morphological changes toward apoptosis in TSTC but not in TRTC or HNTC. However, GDNF significantly compensated TZMB-mediated TSTC cell loss and promoted growth by 37 and 50%, respectively, in TSTC and TRTC. Inhibition of SRC by Saracatinib (SARC) blocked GDNF function and accelerated TZMB-mediated cell death in TSTC, but GDNF continued promoting TRTC growth. These changes paralleled with expression levels of the key molecules involved in growth and apoptosis. Collectively, we found in our xenograft samples that firstly SRC mediates GDNF pro-survival functions by bridging RET-HER2 crosstalk in TZMB-responsive BC tumors. Secondly, SARC-TZMB interactions can synergistically eradicate such tumor cells; and thirdly, GDNF can support antibody resistance by acting independent from SRC in tumors with poor HER2 response to TZMB therapy.
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Pazhoohesh Blvd, Tehran-Karaj HWY Kilometer 15, PO BOX 14965/161, Tehran, Iran. mossa65@nigeb.ac.ir.
authors.forename: Mossa
authors.initials: M
authors.lastname: Gardaneh
authors.affiliation: Department of Stem Cells and Regenerative Medicine, Faculty of Medical Biotechnology, National Institute of Genetic Engineering and Biotechnology (NIGEB), Pazhoohesh Blvd, Tehran-Karaj HWY Kilometer 15, PO BOX 14965/161, Tehran, Iran.
authors.forename: Sahar
authors.initials: S
authors.lastname: Shojaei
authors.affiliation: Department of Surgery, Tehran University of Medical Sciences, Tehran, Iran.
authors.forename: Ahmad
authors.initials: A
authors.lastname: Kaviani
authors.affiliation: NIH Undiagnosed Diseases Program, National Human Genome Research Institute (NHGRI), National Institute of Health (NIH), Bethesda, MD, USA.|Department of Medical Genetics and Molecular Biology, Faculty of Medicine, Iran University of Medical Sciences (IUMS), Tehran, Iran.
authors.forename: Babak
authors.initials: B
authors.lastname: Behnam
mesh_terms: D000818:Animals; D000074322:Antineoplastic Agents, Immunological / Q000494:pharmacology*; D017209:Apoptosis; D052117:Benzodioxoles / Q000494:pharmacology; D015415:Biomarkers; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D051927:CD24 Antigen / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000494:pharmacology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D011799:Quinazolines / Q000494:pharmacology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000074322:Antineoplastic Agents, Immunological; D052117:Benzodioxoles; D015415:Biomarkers; D051927:CD24 Antigen; D051100:Glial Cell Line-Derived Neurotrophic Factor; D018960:Hyaluronan Receptors; D051096:Proto-Oncogene Proteins c-ret; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D019061:src-Family Kinases; C515233:saracatinib
keywords: Breast cancer; GDNF; HER2; RET; SRC; Trastuzumab