title: Targeting mixed lineage kinases in ER-positive breast cancer cells leads to G2/M cell cycle arrest and apoptosis.
abstract: Estrogen receptor (ER)-positive tumors represent the most common type of breast cancer, and ER-targeted therapies such as antiestrogens and aromatase inhibitors have therefore been widely used in breast cancer treatment. While many patients have benefited from these therapies, both innate and acquired resistance continue to be causes of treatment failure. Novel targeted therapeutics that could be used alone or in combination with endocrine agents to treat resistant tumors or to prevent their development are therefore needed. In this report, we examined the effects of inhibiting mixed-lineage kinase (MLK) activity on ER-positive breast cancer cells and non-tumorigenic mammary epithelial cells. Inhibition of MLK activity with the pan-MLK inhibitor CEP-1347 blocked cell cycle progression in G2 and early M phase, and induced apoptosis in three ER-positive breast cancer cell lines, including one with acquired antiestrogen resistance. In contrast, it had no effect on the cell cycle or apoptosis in two non-tumorigenic mammary epithelial cell lines. CEP-1347 treatment did not decrease the level of active ERK or p38 in any of the cell lines tested. However, it resulted in decreased JNK and NF-κB activity in the breast cancer cell lines. A JNK inhibitor mimicked the effects of CEP-1347 in breast cancer cells, and overexpression of c-Jun rescued CEP-1347-induced Bax expression. These results indicate that proliferation and survival of ER-positive breast cancer cells are highly dependent on MLK activity, and suggest that MLK inhibitors may have therapeutic efficacy for ER-positive breast tumors, including ones that are resistant to current endocrine therapies.
authors.affiliation: Department of Microbiology and Molecular Genetics, Michigan State University, East Lansing, MI, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Wang
authors.forename: Kathleen A
authors.initials: KA
authors.lastname: Gallo
authors.forename: Susan E
authors.initials: SE
authors.lastname: Conrad
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D002227:Carbazoles / Q000494:pharmacology; D048708:Cell Growth Processes / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D059566:M Phase Cell Cycle Checkpoints / Q000187:drug effects / Q000502:physiology; D020930:MAP Kinase Kinase Kinases; D020935:MAP Kinase Signaling System / Q000187:drug effects; D061986:MCF-7 Cells; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000096:biosynthesis / Q000378:metabolism*; D014162:Transfection; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D002227:Carbazoles; D048031:JNK Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; D020928:Mitogen-Activated Protein Kinases; D047428:Protein Kinase Inhibitors; D011960:Receptors, Estrogen; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C106592:3,9-bis((ethylthio)methyl)-K-252a
references.citation: Neurology. 2004 Jan 27;62(2):330-2
references.pmid: 14745084
references.citation: Clin Cancer Res. 2004 Jan 1;10(1 Pt 2):331S-6S
references.pmid: 14734488
references.citation: Neurology. 2007 Oct 9;69(15):1480-90
references.pmid: 17881719
references.citation: Nat Rev Mol Cell Biol. 2002 Sep;3(9):663-72
references.pmid: 12209126
references.citation: Cancer Res. 1999 May 1;59(9):2195-202
references.pmid: 10232608
references.citation: J Mammary Gland Biol Neoplasia. 1998 Jan;3(1):49-61
references.pmid: 10819504
references.citation: Annu Rev Med. 2011;62:233-47
references.pmid: 20887199
references.citation: Cancer J. 2002 Jul-Aug;8(4):328-36
references.pmid: 12184411
references.citation: FASEB J. 1995 Jun;9(9):726-35
references.pmid: 7601337
references.citation: Cancer Res. 2012 Aug 15;72(16):4130-40
references.pmid: 22700880
references.citation: Endocrinology. 2000 Jan;141(1):396-405
references.pmid: 10614662
references.citation: J Biol Chem. 2001 Jul 6;276(27):25302-8
references.pmid: 11325962
references.citation: Cancer Res. 1997 Oct 1;57(19):4285-300
references.pmid: 9331090
references.citation: Breast Cancer Res Treat. 2012 Aug;135(1):67-78
references.pmid: 22527100
references.citation: Ann Oncol. 2012 Oct;23(10):2526-2535
references.pmid: 22553196
references.citation: Mol Cancer Ther. 2005 Jan;4(1):33-41
references.pmid: 15657351
references.citation: Nucleic Acids Res. 1983 Mar 11;11(5):1475-89
references.pmid: 6828386
references.citation: Cancer Res. 1997 Aug 15;57(16):3486-93
references.pmid: 9270017
references.citation: CA Cancer J Clin. 2011 Mar-Apr;61(2):69-90
references.pmid: 21296855
references.citation: Oncogene. 2012 Aug 23;31(34):3889-900
references.pmid: 22139075
references.citation: J Neurosci. 2002 Jan 1;22(1):103-13
references.pmid: 11756493
references.citation: J Mammary Gland Biol Neoplasia. 2008 Dec;13(4):471-83
references.pmid: 19023648
references.citation: J Neurosci. 2001 Jul 15;21(14):4949-57
references.pmid: 11438570
references.citation: Breast Cancer Res Treat. 2007;105 Suppl 1:75-89
references.pmid: 17912638
references.citation: Clin Cancer Res. 2007 Feb 15;13(4):1076-82
references.pmid: 17317814
references.citation: Mol Endocrinol. 2010 Mar;24(3):598-607
references.pmid: 20150185
references.citation: Nature. 2001 Mar 1;410(6824):37-40
references.pmid: 11242034
references.citation: Cancer Res. 1998 Sep 15;58(18):4071-4
references.pmid: 9751612
references.citation: Mol Cell Biol. 2000 Apr;20(7):2556-68
references.pmid: 10713178
references.citation: Exp Cell Res. 2012 Aug 15;318(14):1641-8
references.pmid: 22652451
references.citation: Nat Cell Biol. 2002 May;4(5):E131-6
references.pmid: 11988758
references.citation: Nat Rev Cancer. 2009 Aug;9(8):537-49
references.pmid: 19629069
references.citation: Oncogene. 2010 Aug 5;29(31):4399-411
references.pmid: 20514022
references.citation: Oncogene. 2008 Oct 20;27(48):6245-51
references.pmid: 18931691
references.citation: N Engl J Med. 2005 Oct 20;353(16):1659-72
references.pmid: 16236737
references.citation: J Neurochem. 2004 Jan;88(2):469-80
references.pmid: 14690535
references.citation: Breast Cancer Res Treat. 2011 Jan;125(2):457-65
references.pmid: 21110084
references.citation: Nat Cell Biol. 2004 Aug;6(8):770-6
references.pmid: 15258589
references.citation: Cell Signal. 2006 Jan;18(1):93-104
references.pmid: 15923109