title: Transactivator of transcription-tagged cell cycle and apoptosis regulatory protein-1 peptides suppress the growth of human breast cancer cells in vitro and in vivo.
abstract: Deregulated signaling by the epidermal growth factor receptor family of proteins is encountered in human malignancies including breast cancer. Cell cycle and apoptosis-regulatory protein-1 (CARP-1), a novel, perinuclear phosphoprotein, is a regulator of apoptosis signaling by epidermal growth factor receptors. CARP-1 expression is diminished in human breast cancers, and correlates inversely with human breast cancer grades which could be attributed to increased methylation. The expression of CARP-1, on the other hand, interferes with the ability of human breast cancer cells to invade through the matrigel-coated membranes, to form colonies in the soft agar, and to grow as s.c. tumors in severe combined immunodeficiency (SCID) mice. To test whether CARP-1 is a suppressor of human breast cancer growth, we generated transactivator of transcription (TAT)-tagged CARP-1 peptides. Treatment of human breast cancer cells with affinity purified, TAT-CARP-1 1-198, 197-454, and 896-1150 peptides caused inhibition of human breast cancer cell proliferation and elevated apoptosis. In contrast, TAT-tagged enhanced green fluorescent protein or CARP-1 (1-198(Y192/F)) peptide failed to inhibit cell proliferation or induce apoptosis. Apoptosis by CARP-1 peptides, with the exception of CARP-1 (1-198(Y192/F)), involves the activation of p38 stress-activated protein kinase and caspase-9. Moreover, administration of TAT-CARP-1 (1-198), but not TAT-tagged enhanced green fluorescent protein or TAT-CARP-1 (1-198(Y192/F)), inhibits growth of human breast cancer cell-derived tumor xenografts in SCID mice. We conclude that CARP-1 is a suppressor of human breast cancer growth, and its expression is diminished in tumors, in part, by methylation-dependent silencing.
authors.affiliation: Veterans Affairs Medical Center, Wayne State University, Detroit, Michigan 48201, USA.
authors.forename: Liyue
authors.initials: L
authors.lastname: Zhang
authors.forename: Edi
authors.initials: E
authors.lastname: Levi
authors.forename: Pralay
authors.initials: P
authors.lastname: Majumder
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Yu
authors.forename: Amro
authors.initials: A
authors.lastname: Aboukameel
authors.forename: Jianhua
authors.initials: J
authors.lastname: Du
authors.forename: Hu
authors.initials: H
authors.lastname: Xu
authors.forename: Ramzi
authors.initials: R
authors.lastname: Mohammad
authors.forename: James S
authors.initials: JS
authors.lastname: Hatfield
authors.forename: Anil
authors.initials: A
authors.lastname: Wali
authors.forename: Volkan
authors.initials: V
authors.lastname: Adsay
authors.forename: Adhip P N
authors.initials: AP
authors.lastname: Majumdar
authors.forename: Arun K
authors.initials: AK
authors.lastname: Rishi
mesh_terms: D000362:Agar / Q000737:chemistry; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D001943:Breast Neoplasms / Q000188:drug therapy*; D018797:Cell Cycle Proteins / Q000378:metabolism / Q000502:physiology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005260:Female; D020868:Gene Silencing; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D015533:Transcriptional Activation
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C477529:CCAR1 protein, human; D018797:Cell Cycle Proteins; D049452:Green Fluorescent Proteins; D000362:Agar