Growth hormone-releasing hormone induced transactivation of epidermal growth factor receptor in human triple-negative breast cancer cells.
Triple-negative breast cancer (TNBC) is a subset of breast cancers which is negative for expression of estrogen and progesterone receptors and human epidermal growth factor receptor-2 (HER2). Chemotherapy is currently the only form of treatment for women with TNBC. Growth hormone-releasing hormone (GHRH) and epidermal growth factor (EGF) are autocrine/paracrine growth factors in breast cancer and a substantial proportion of TNBC expresses receptors for GHRH and EGF. The aim of this study was to evaluate the interrelationship between both these signaling pathways in MDA-MB-468 human TNBC cells. We evaluated by Western blot assays the effect of GHRH on transactivation of EGF receptor (EGFR) as well as the elements implicated. We assessed the effect of GHRH on migration capability of MDA-MB-468 cells as well as the involvement of EGFR in this process by means of wound-healing assays. Our findings demonstrate that in MDA-MB-468 cells the stimulatory activity of GHRH on tyrosine phosphorylation of EGFR is exerted by two different molecular mechanisms: i) through GHRH receptors, GHRH stimulates a ligand-independent activation of EGFR involving at least cAMP/PKA and Src family signaling pathways; ii) GHRH also stimulates a ligand-dependent activation of EGFR implicating an extracellular pathway with an important role for metalloproteinases. The cross-talk between EGFR and GHRHR may be impeded by combining drugs acting upon GHRH receptors and EGFR family members. This combination of GHRH receptors antagonists with inhibitors of EGFR signalling could enhance the efficacy of both types of agents as well as reduce their doses increasing therapeutic benefits in management of human breast cancer.
Department of Systems of Biology, University of Alcala, Alcala de Henares, Spain.
Eva
E
Vacas
Department of Systems of Biology, University of Alcala, Alcala de Henares, Spain.
Laura
L
Muñoz-Moreno
Obstetrics and Gynaecology Department, Principe de Asturias Hospital, Alcalá de Henares University, Alcalá de Henares, Madrid, Spain.
Pedro L
PL
Valenzuela
Department of Systems of Biology, University of Alcala, Alcala de Henares, Spain.
Juan C
JC
Prieto
Veterans Administration Medical Center and Departments of Pathology and Medicine, Division of Oncology and Hematology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine and South Florida Veterans Affairs Foundation for Research and Education, Miami, FL, USA.
Andrew V
AV
Schally
Department of Systems of Biology, University of Alcala, Alcala de Henares, Spain.
María J
MJ
Carmena
Department of Systems of Biology, University of Alcala, Alcala de Henares, Spain. Electronic address: ana.bajo@uah.es.
Ana M
AM
Bajo
D045744:Cell Line, Tumor; D002465:Cell Movement; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D013007:Growth Hormone-Releasing Hormone / Q000502:physiology*; D006801:Humans; D020782:Matrix Metalloproteinases / Q000378:metabolism; D015398:Signal Transduction; D015533:Transcriptional Activation; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D019061:src-Family Kinases / Q000378:metabolism
D013007:Growth Hormone-Releasing Hormone; C512478:EGFR protein, human; D066246:ErbB Receptors; D019061:src-Family Kinases; D020782:Matrix Metalloproteinases
Cell migration; EGFR; GHRH; GHRH antagonist; Transactivation; Triple-negative breast cancer