Regulation of miRNA-29c and its downstream pathways in preneoplastic progression of triple-negative breast cancer.
Little is understood about the early molecular drivers of triple-negative breast cancer (TNBC), making the identification of women at risk and development of targeted therapy for prevention significant challenges. By sequencing a TNBC cell line-based breast cancer progression model we have found that miRNA-29c is progressively lost during TNBC tumorigenesis. In support of the tumor suppressive role of miRNA 29c, we found that low levels predict poor overall patient survival and, conversely, that ectopic expression of miRNA-29c in preneoplastic cell models inhibits growth. miRNA-29c exerts its growth inhibitory effects through direct binding and regulation of TGFB-induced factor homeobox 2 (TGIF2), CAMP-responsive element binding protein 5 (CREB5), and V-Akt murine thymoma viral oncogene homolog 3 (AKT3). miRNA-29c regulation of these gene targets seems to be functionally relevant, as TGIF2, CREB5, and AKT3 were able to rescue the inhibition of cell proliferation and colony formation caused by ectopic expression of miRNA-29c in preneoplastic cells. AKT3 is an oncogene of known relevance in breast cancer, and as a proof of principle we show that inhibition of phosphoinositide 3-kinase (PI3K) activity, a protein upstream of AKT3, suppressed proliferation in TNBC preneoplastic cells. We explored additional opportunities for prevention of TNBC by studying the regulation of miRNA-29c and identified DNA methylation to have a role in the inhibition of miRNA-29c during TNBC tumorigenesis. Consistent with these observations, we found 5 aza-cytadine to relieve the suppression of miRNA-29c. Together, these results demonstrate that miRNA-29c loss plays a key role in the early development of TNBC.
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Anjana
A
Bhardwaj
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Harpreet
H
Singh
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Kimal
K
Rajapakshe
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Kazunoshin
K
Tachibana
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Nivetha
N
Ganesan
Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Yinghong
Y
Pan
Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
Preethi H
PH
Gunaratne
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
Cristian
C
Coarfa
Department of Breast Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Isabelle
I
Bedrosian
D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D001940:Breast / Q000378:metabolism / Q000473:pathology*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000473:pathology*; D049109:Cell Proliferation; D051699:Cyclic AMP Response Element-Binding Protein A / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009367:Neoplasm Staging; D011230:Precancerous Conditions / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000473:pathology*; D014407:Tumor Cells, Cultured
D014408:Biomarkers, Tumor; C497102:CREB5 protein, human; D051699:Cyclic AMP Response Element-Binding Protein A; D018398:Homeodomain Proteins; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D012097:Repressor Proteins; C414585:TGIF2 protein, human; C491754:AKT3 protein, human; D051057:Proto-Oncogene Proteins c-akt
DNA methylation; TNBC; miRNA-29c; next generation RNA sequencing; prevention