TY - JOUR
T1 - Atf3‐induced mammary tumors exhibit molecular features of human basal‐like breast cancer
AU - Yan, Leqin
AU - Gaddis, Sally
AU - Coletta, Luis Della
AU - Repass, John
AU - Powell, Katherine Leslie
AU - Simper, Melissa S.
AU - Chen, Yueping
AU - Byrom, Michelle
AU - Zhong, Yi
AU - Lin, Kevin
AU - Liu, Bin
AU - Lu, Yue
AU - Shen, Jianjun
AU - Macleod, Michael C.
N1 - Funding Information:
Funding: This study was supported by NIH R01 CA16620 (M.C.M.), by Center grants NIH P30 CA016672 and NIH P30 ES007784, and by Cancer Prevention and Research Institute of Texas Awards CPRIT RP170002 (J.S.). The funders had no role in study design, data collection, and anal‐ ysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/3/1
Y1 - 2021/3/1
N2 - Basal‐like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem‐cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aber-rantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β‐catenin signaling pathway. Here, we used RNA‐Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3‐derived mammary tu-mors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem‐cell‐related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.
AB - Basal‐like breast cancer (BLBC) is an aggressive and deadly subtype of human breast cancer that is highly metastatic, displays stem‐cell like features, and has limited treatment options. Therefore, developing and characterizing preclinical mouse models with tumors that resemble BLBC is important for human therapeutic development. ATF3 is a potent oncogene that is aber-rantly expressed in most human breast cancers. In the BK5.ATF3 mouse model, overexpression of ATF3 in the basal epithelial cells of the mammary gland produces tumors that are characterized by activation of the Wnt/β‐catenin signaling pathway. Here, we used RNA‐Seq and microRNA (miRNA) microarrays to better define the molecular features of BK5.ATF3‐derived mammary tu-mors. These analyses showed that these tumors share many characteristics of human BLBC including reduced expression of Rb1, Esr1, and Pgr and increased expression of Erbb2, Egfr, and the genes encoding keratins 5, 6, and 17. An analysis of miRNA expression revealed reduced levels of Mir145 and Mir143, leading to the upregulation of their target genes including both the pluripotency factors Klf4 and Sox2 as well as the cancer stem‐cell‐related gene Kras. Finally, we show through knock-down experiments that ATF3 may directly modulate MIR145/143 expression. Taken together, our results indicate that the ATF3 mouse mammary tumor model could provide a powerful model to define the molecular mechanisms leading to BLBC, identify the factors that contribute to its aggressiveness, and, ultimately, discover specific genes and gene networks for therapeutic targeting.
KW - ATF3
KW - Basal‐like
KW - Breast cancer
KW - MiRNA
KW - Mir143
KW - Mir145
KW - Mouse model
KW - RNA‐Seq
UR - http://www.scopus.com/inward/record.url?scp=85101499486&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85101499486&partnerID=8YFLogxK
U2 - 10.3390/ijms22052353
DO - 10.3390/ijms22052353
M3 - Article
C2 - 33652981
AN - SCOPUS:85101499486
SN - 1661-6596
VL - 22
SP - 1
EP - 18
JO - International journal of molecular sciences
JF - International journal of molecular sciences
IS - 5
M1 - 2353
ER -