Atf3‐induced mammary tumors exhibit molecular features of human basal‐like breast cancer

Leqin Yan, Sally Gaddis, Luis Della Coletta, John Repass, Katherine Leslie Powell, Melissa S. Simper, Yueping Chen, Michelle Byrom, Yi Zhong, Kevin Lin, Bin Liu, Yue Lu, Jianjun Shen, Michael C. Macleod

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number2353
Pages (from-to)1-18
Number of pages18
JournalInternational journal of molecular sciences
Volume22
Issue number5
DOIs
StatePublished - Mar 1 2021

Keywords

  • ATF3
  • Basal‐like
  • Breast cancer
  • MiRNA
  • Mir143
  • Mir145
  • Mouse model
  • RNA‐Seq

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

MD Anderson CCSG core facilities

  • Research Animal Support Facility

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