LncRNAs exhibit subtype-specific expression, survival associations, and cancer-promoting effects in breast cancer.

Long non-coding RNAs (lncRNAs) play important roles in cancer progression, influencing processes such as invasion, metastasis, and drug resistance. Their reported cell type-dependent expression patterns suggest the potential for specialized functions in specific contexts. In breast cancer, lncRNA expression has been associated with different subtypes, highlighting their relevance in disease heterogeneity. However, our understanding of lncRNA function within breast cancer subtypes remains limited, warranting further investigation. We conducted a comprehensive analysis using the TANRIC dataset derived from the TCGA-BRCA cohort, profiling the expression, patient survival associations and immune cell type correlations of 12,727 lncRNAs across subtypes. Our findings revealed subtype-specific associations of lncRNAs with patient survival, tumor infiltrating lymphocytes and other immune cells. Targeting of lncRNAs exhibiting subtype-specific survival associations and expression in a panel of breast cancer cells demonstrated a selective reduction in cell proliferation within their associated subtype, supporting subtype-specific functions of certain lncRNAs. Characterization of HER2 + -specific lncRNA LINC01269 and TNBC-specific lncRNA AL078604.2 showed nuclear localization and altered expression of hundreds of genes enriched in cancer-promoting processes, including apoptosis, cell proliferation and immune cell regulation. This work emphasizes the importance of considering the heterogeneity of breast cancer subtypes and the need for subtype-specific analyses to fully uncover the relevance and potential impact of lncRNAs. Collectively, these findings demonstrate the contribution of lncRNAs to the distinct molecular, prognostic, and cellular composition of breast cancer subtypes.

ALDH1A3 promotes invasion and metastasis in triple-negative breast cancer by regulating the plasminogen activation pathway.

Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell marker that promotes metastasis. Triple-negative breast cancer (TNBC) progression has been linked to ALDH1A3-induced gene expression changes. 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, a process that 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. The ALDH1A3 product all-trans-retinoic acid similarly increased tPA and plasmin activity. The 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 and lymph node metastasis. These results identify the ALDH1A3-tPA-plasmin axis as a key contributor to breast cancer progression.

The Expanding Role of Cancer Stem Cell Marker ALDH1A3 in Cancer and Beyond.

Aldehyde dehydrogenase 1A3 (ALDH1A3) is one of 19 ALDH enzymes expressed in humans, and it is critical in the production of hormone receptor ligand retinoic acid (RA). We review the role of ALDH1A3 in normal physiology, its identification as a cancer stem cell marker, and its modes of action in cancer and other diseases. ALDH1A3 is often over-expressed in cancer and promotes tumor growth, metastasis, and chemoresistance by altering gene expression, cell signaling pathways, and glycometabolism. The increased levels of ALDH1A3 in cancer occur due to genetic amplification, epigenetic modifications, post-transcriptional regulation, and post-translational modification. Finally, we review the potential of targeting ALDH1A3, with both general ALDH inhibitors and small molecules specifically designed to inhibit ALDH1A3 activity.