Abstract
Notch3 and GATA binding protein 3 (GATA-3) have been, individually, shown to maintain luminal phenotype and inhibit epithelial–mesenchymal transition (EMT) in breast cancers. In the present study, we report that Notch3 expression positively correlates with that of GATA-3, and both are associated with estrogen receptor-α (ERα) expression in breast cancer cells. We demonstrate in vitro and in vivo that Notch3 suppressed EMT and breast cancer metastasis by activating GATA-3 transcription. Furthermore, Notch3 knockdown downregulated GATA-3 and promoted EMT; while overexpression of Notch3 intracellular domain upregulated GATA-3 and inhibited EMT, leading to a suppression of metastasis in vivo. Moreover, inhibition or overexpression of GATA-3 partially reversed EMT or mesenchymal–epithelial transition induced by Notch3 alterations. In breast cancer patients, high GATA-3 expression is associated with higher Notch3 expression and lower lymph node metastasis, especially for hormone receptor (HR) positive cancers. Herein, we demonstrate a novel mechanism whereby Notch3 inhibit EMT by transcriptionally upregulating GATA-3 expression, at least in part, leading to the suppression of cancer metastasis in breast cancers. Our findings expand our current knowledge on Notch3 and GATA-3's roles in breast cancer metastasis.
Highlights
Breast cancer remains the most frequent cancer of female and the principal contributing to the cancer associate mortality in women all around the world[1]
Immunofluorescence further confirmed that Notch[3] and GATA binding protein 3 (GATA-3) are primarily expressed in MCF-7 and T47D cells
estrogen receptor-α (ERα)-positive, luminal subtype, or welldifferentiated epithelial breast cancer expresses a notably high level of GATA-3 compared to estrogen receptor (ER)-negative invasive breast cancer[31,32]
Summary
Breast cancer remains the most frequent cancer of female and the principal contributing to the cancer associate mortality in women all around the world[1]. Breast cancers are usually divided into those that are hormone-dependent and those that are hormoneindependent according to their estrogen receptor (ER) status. The ER-positive subtype of breast cancers features cells that are sensitive to estrogen ablation, which contributes to its generally favorable prognosis. Many factors may modulate ER expression, such as GATA-3 and pS2, as well post-transcriptional modifications. Among the GATA family (GATA 1–6), GATA-3 is the most abundantly expressed in luminal epithelial cells. GATA-3 is essential for the development of human mammary gland and the differentiation breast cancer cell[6,7,8,9]. A loss of expression of the ERα is observed in GATA-3 knockout mice[9]. With regard to breast cancer, a positive feedback loop has been identified to affect GATA-3 and ERα regulation[6]; both GATA-3 and ERα can be used as markers to predict patient responses to endocrine treatment of breast cancer 6
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