MTDH activation by 8q22 genomic gain promotes chemoresistance and metastasis of poor-prognosis breast cancer.
Targeted therapy for metastatic diseases relies on the identification of functionally important metastasis genes from a large number of random genetic alterations. Here we use a computational algorithm to map minimal recurrent genomic alterations associated with poor-prognosis breast cancer. 8q22 genomic gain was identified by this approach and validated in an extensive collection of breast tumor samples. Regional gain of 8q22 elevates expression of the metastasis gene metadherin (MTDH), which is overexpressed in more than 40% of breast cancers and is associated with poor clinical outcomes. Functional characterization of MTDH revealed its dual role in promoting metastatic seeding and enhancing chemoresistance. These findings establish MTDH as an important therapeutic target for simultaneously enhancing chemotherapy efficacy and reducing metastasis risk.
Hu
Guohong
G
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Chong
Robert A
RA
Yang
Qifeng
Q
Wei
Yong
Y
Blanco
Mario A
MA
Li
Feng
F
Reiss
Michael
M
Au
Jessie L-S
JL
Haffty
Bruce G
BG
Kang
Yibin
Y
D000444:Aldehyde Dehydrogenase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D015815:Cell Adhesion Molecules / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics*; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D008565:Membrane Proteins; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000235:genetics / Q000473:pathology; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met; D016601:RNA-Binding Proteins; D017978:Receptors, Growth Factor / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D023041:Xenograft Model Antitumor Assays
D015815:Cell Adhesion Molecules; C483039:MTDH protein, human; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D016601:RNA-Binding Proteins; D017978:Receptors, Growth Factor; C480021:ALDH3A1 protein, human; D000444:Aldehyde Dehydrogenase; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met