title: Loss of tumor suppressor Merlin in advanced breast cancer is due to post-translational regulation.
abstract: Unlike malignancies of the nervous system, there have been no mutations identified in Merlin in breast cancer. As such, the role of the tumor suppressor, Merlin, has not been investigated in breast cancer. We assessed Merlin expression in breast cancer tissues by immunohistochemistry and by real-time PCR. The expression of Merlin protein (assessed immunohistochemically) was significantly decreased in breast cancer tissues (although the transcript levels were comparable) simultaneous with increased expression of the tumor-promoting protein, osteopontin (OPN). We further demonstrate that the loss of Merlin in breast cancer is brought about, in part, due to OPN-initiated Akt-mediated phosphorylation of Merlin leading to its proteasomal degradation. Restoring expression of Merlin resulted in reduced malignant attributes of breast cancer, characterized by reduced invasion, migration, motility, and impeded tumor (xenograft) growth in immunocompromised mice. The possibility of developing a model using the relationship between OPN and Merlin was tested with a logistic regression model applied to immunohistochemistry data. This identified consistent loss of immunohistochemical expression of Merlin in breast tumor tissues. Thus, we demonstrate for the first time a role for Merlin in impeding breast malignancy, identify a novel mechanism for the loss of Merlin protein in breast cancer, and have developed a discriminatory model using Merlin and OPN expression in breast tumor tissues.
authors.affiliation: Department of Oncologic Sciences, Mitchell Cancer Institute, Mobile, Alabama 36604, USA.
authors.forename: K Adam
authors.initials: KA
authors.lastname: Morrow
authors.forename: Shamik
authors.initials: S
authors.lastname: Das
authors.forename: Brandon J
authors.initials: BJ
authors.lastname: Metge
authors.forename: Keqiang
authors.initials: K
authors.lastname: Ye
authors.forename: Madhuri S
authors.initials: MS
authors.lastname: Mulekar
authors.forename: J Allan
authors.initials: JA
authors.lastname: Tucker
authors.forename: Rajeev S
authors.initials: RS
authors.lastname: Samant
authors.forename: Lalita A
authors.initials: LA
authors.lastname: Shevde
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002465:Cell Movement; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008954:Models, Biological; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D025581:Neurofibromin 2 / Q000235:genetics / Q000378:metabolism*; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000235:genetics; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D025581:Neurofibromin 2; D053495:Osteopontin; D051057:Proto-Oncogene Proteins c-akt