TRIPLE-NEGATIVE BREAST CANCER STEM CELL MARKER ALDH1A3 REGULATES THE PLASMINOGEN PATHWAY TO PROMOTE INVASION AND METASTASIS

Abstract

Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that also increases tumour growth, promotes metastasis, and contributes to chemoresistance. Metastasis of triple-negative breast cancer (TNBC) has been linked to gene expression changes induced by ALDH1A3. To investigate the mechanism of ALDH1A3-mediated breast cancer metastasis, we assessed the effect of ALDH1A3 on the expression of proteases and the regulators of proteases that degrade the extracellular matrix, which is essential for invasion and metastasis. This revealed that ALDH1A3 regulates the plasminogen activation pathway; it increased the levels and activity of tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA). This resulted in a corresponding increase in the activity of serine protease plasmin, the enzymatic product of tPA and uPA. All-trans-retinoic acid, which is produced by ALDH1A3 and is a hormone receptor ligand, similarly led to an increased tPA and plasmin activity. DNA methylation also regulates tPA at the gene level where CpG methylation near the transcription start site prevents expression of tPA. Increased invasion of TNBC cells by ALDH1A3 was plasminogen-dependent. In patient tumours, ALDH1A3 and tPA are co-expressed and their combined expression correlated with the TNBC subtype, high tumour grade, and recurrent metastatic disease. Knockdown of tPA in TNBC cells inhibited plasmin generation, invasion, and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.