Tumor suppressor function of RUNX3 in breast cancer

Abstract

Emerging evidence indicates that RUNX3 is a tumor suppressor in breast cancer. RUNX3 is frequently inactivated in human breast cancer cell lines and cancer samples by hemizygous deletion of the Runx3 gene, hypermethylation of the Runx3 promoter, or cytoplasmic sequestration of RUNX3 protein. Inactivation of RUNX3 is associated with the initiation and progression of breast cancer. Female Runx3(+/-) mice spontaneously develop ductal carcinoma, and overexpression of RUNX3 inhibits the proliferation, tumorigenic potential, and invasiveness of breast cancer cells. This review is intended to summarize these findings and discuss the tumor suppressor function of RUNX3 in breast cancer.

Fig. 1

Inactivation of tumor suppressor RUNX3 in breast cancer. (A) Hypermethylation of Runx3 promoter. Estrogen or other cellular stress might induce hypermethylation by facilitating the recruitment or activation of histone- or DNA-modifying enzymes. Deacetylation of histones by HDACs or the concomitant methylation of histones by HMTs may result in the recruitment of the DNMT-containing repression complex, which induces the methylation of DNA and the silencing of Runx3. Ac=acetylation, Me=methylation, ○=CpG, ●=mCpG. (B) Inactivation of RUNX3 by protein mislocalization. Cytoplasmic relocalization of RUNX3 might result from 1) the masking of the NLS by a binding partner; 2) Src- or Pim-1-mediated RUNX3 phosphorylation; or 3) HDACs- or G9a-mediated deacetylation or methylation of RUNX3. Sequestration of RUNX3 in the cytoplasm prevents the expression of RUNX3 target genes.

Fig. 2

RUNX3 integrates with various cellular signaling pathways for its tumor suppressor activity. (A) RUNX3 suppresses ERα signaling in breast cancer. Binding of RUNX3 to ERα induces the ubiquitination and degradation of ERα by an unidentified E3 ligase (X). The low levels of ERα maintain the normal growth of mammary epithelial cells. When RUNX3 is inactivated, the cellular levels of ERα are enhanced, leading to the enhanced response to estradiol (E₂), the hyperproliferation of breast cells, and eventually the formation of breast cancer. (B) RUNX3 could either act as a downstream target of a tumor suppressor pathway (e.g, TGF-β signaling) or function as a suppressor in an oncogenic pathway (e.g., Wnt signaling) to regulate cell proliferation, apoptosis, and cell migration. By interacting with various signaling pathways, RUNX3 might also have a role in breast cancer carcinogenesis by regulating the EMT and breast cancer stem cell development.