Geminin overexpression promotes imatinib sensitive breast cancer: a novel treatment approach for aggressive breast cancers, including a subset of triple negative.
Breast cancer is the second leading cause of cancer-related deaths in women. Triple negative breast cancer (TNBC) is an aggressive subtype that affects 10-25% mostly African American women. TNBC has the poorest prognosis of all subtypes with rapid progression leading to mortality in younger patients. So far, there is no targeted treatment for TNBC. To that end, here we show that c-Abl is one of several tyrosine kinases that phosphorylate and activate geminin's ability to promote TNBC. Analysis of >800 breast tumor samples showed that geminin is overexpressed in ∼50% of all tumors. Although c-Abl is overexpressed in ∼90% of all tumors, it is only nuclear in geminin overexpressing tumors. In geminin-negative tumors, c-Abl is only cytoplasmic. Inhibiting c-Abl expression or activity (using imatinib or nilotinib) prevented geminin Y150 phosphorylation, inactivated the protein, and most importantly converted overexpressed geminin from an oncogene to an apoptosis inducer. In pre-clinical orthotopic breast tumor models, geminin-overexpressing cells developed aneuploid and invasive tumors, which were suppressed when c-Abl expression was blocked. Moreover, established geminin overexpressing orthotopic tumors regressed when treated with imatinib or nilotinib. Our studies support imatinib/nilotonib as a novel treatment option for patients with aggressive breast cancer (including a subset of TNBCs)-overexpressing geminin and nuclear c-Abl.
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America; Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Zannel
Z
Blanchard
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Nicole
N
Mullins
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Pavani
P
Ellipeddi
Department of Pathology, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Janice M
JM
Lage
Department of Surgery, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Shawn
S
McKinney
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Rana
R
El-Etriby
Center of Biostatistics and Bioinformatics, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Xu
X
Zhang
Center for Bioinformatics & Computational Biology, Department of Biology, Jackson State University, Jackson, Mississippi, United States of America.
Raphael
R
Isokpehi
Cancer Research Center of Hawaii, University of Hawaii, Honolulu, Hawaii, United States of America.
Brenda
B
Hernandez
Cancer Institute, University of Mississippi Medical Center, Jackson, Mississippi, United States of America; Department of Biochemistry, University of Mississippi Medical Center, Jackson, Mississippi, United States of America.
Wael M
WM
Elshamy
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000627:therapeutic use*; D005260:Female; D064248:Geminin / Q000378:metabolism*; D006801:Humans; D000068877:Imatinib Mesylate; D010766:Phosphorylation; D010879:Piperazines / Q000627:therapeutic use*; D016315:Proto-Oncogene Proteins c-abl / Q000378:metabolism; D011743:Pyrimidines / Q000627:therapeutic use*; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism*
D000970:Antineoplastic Agents; D001549:Benzamides; D064248:Geminin; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D016315:Proto-Oncogene Proteins c-abl