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Treatment decisions for breast cancer are based on staging and hormone receptor expression and include chemotherapies and endocrine therapy. While effective in many cases, some breast cancers are resistant to therapy, metastasize and recur, leading to eventual death. Higher percentages of tumor-initiating cancer stem cells (CSCs) may contribute to the increased aggressiveness, chemoresistance, and worse outcomes among breast cancer. This may be particularly true in triple-negative breast cancers (TNBCs) which have higher percentages of CSCs and are associated with worse outcomes. In recent years, increasing numbers of long non-coding RNAs (lncRNAs) have been identified as playing an important role in breast cancer progression and some of these have been specifically associated within the CSC populations of breast cancers. LncRNAs are non-protein-coding transcripts greater than 200 nucleotides which can have critical functions in gene expression regulation. The preclinical evidence regarding lncRNA antagonists for the treatment of cancer is promising and therefore, presents a potential novel approach for treating breast cancer and targeting therapy-resistant CSCs within these tumors. Herein, we summarize the lncRNAs that have been identified as functionally relevant in breast CSCs. Furthermore, our review of the literature and analysis of patient datasets has revealed that many of these breast CSC-associated lncRNAs are also enriched in TNBC. Together, this suggests that these lncRNAs may be playing a particularly important role in TNBC. Thus, certain breast cancer-promoting/CSC-associated lncRNAs could be targeted in the treatment of TNBCs and the CSCs within these tumors should be susceptible to anti-lncRNA therapy.

Introduction Aldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell (CSC) marker and in breast cancer it is associated with triple-negative/basal-like subtypes and aggressive disease. Studies on the mechanisms of ALDH1A3 in cancer have primarily focused on gene expression changes induced by the enzyme; however, its effects on metabolism have thus far been unstudied and may reveal novel mechanisms of pathogenesis. Objective Determine how ALDH1A3 alters the metabolite profile in breast cancer cells and assess potential impacts. Method Triple-negative MDA-MB-231 tumors and cells with manipulated ALDH1A3 levels were assessed by HPLC–MS metabolomics and metabolite data was integrated with transcriptome data. Mice harboring MDA-MB-231 tumors with or without altered ALDH1A3 expression were treated with γ-aminobutyric acid (GABA) or placebo. Effects on tumor growth, and lungs and brain metastasis were quantified by staining of fixed thin sections and quantitative PCR. Breast cancer patient datasets from TCGA, METABRIC and GEO were used to assess the co-expression of GABA pathway genes with ALDH1A3. Results Integrated metabolomic and transcriptome data identified GABA metabolism as a primary dysregulated pathway in ALDH1A3 expressing breast tumors. Both ALDH1A3 and GABA treatment enhanced metastasis. Patient dataset analyses revealed expression association between ALDH1A3 and GABA pathway genes and corresponding increased risk of metastasis. Conclusion This study revealed a novel pathway affected by ALDH1A3, GABA metabolism. Like ALDH1A3 expression, GABA treatment promotes metastasis. Given the clinical use of GABA mimics to relieve chemotherapy-induced peripheral nerve pain, further study of the effects of GABA in breast cancer progression is warranted.

Triple-negative breast cancers (TNBCs) are aggressive, lack targeted therapies and are enriched in cancer stem cells (CSCs). Novel therapies which target CSCs within these tumors would likely lead to improved outcomes for TNBC patients. Long non-coding RNAs (lncRNAs) are potential therapeutic targets for TNBC and CSCs. We demonstrate that lncRNA prostate androgen regulated transcript 1 (PART1) is enriched in TNBCs and in Aldefluorhigh CSCs, and is associated with worse outcomes among basal-like breast cancer patients. Although PART1 is androgen inducible in breast cancer cells, analysis of patient tumors indicates its androgen regulation has minimal clinical impact. Knockdown of PART1 in TNBC cell lines and a patient-derived xenograft decreased cell proliferation, migration, tumor growth, and mammosphere formation potential. Transcriptome analyses revealed that the lncRNA affects expression of hundreds of genes (e.g., myosin-Va, MYO5A; zinc fingers and homeoboxes protein 2, ZHX2). MiRNA 4.0 GeneChip and TaqMan assays identified multiple miRNAs that are regulated by cytoplasmic PART1, including miR-190a-3p, miR-937-5p, miR-22-5p, miR-30b-3p, and miR-6870-5p. We confirmed the novel interaction between PART1 and miR-937-5p. In general, miRNAs altered by PART1 were less abundant than PART1, potentially leading to cell line-specific effects in terms miRNA-PART1 interactions and gene regulation. Together, the altered miRNA landscape induced by PART1 explains most of the protein-coding gene regulation changes (e.g., MYO5A) induced by PART1 in TNBC.

Long non-coding RNA (lncRNA)/microRNA (miRNA)/messenger RNA (mRNA) interactions regulate oncogenesis and tumour suppression in breast cancer. Oncogenic lncRNA/miRNA/mRNA axes may offer novel therapeutic targets; therefore, identifying such axes is a clinically relevant undertaking. To explore miRNAs regulated by oncogenic lncRNAs, we queried the NCBI Gene Expression Omnibus (GEO) database to find datasets that profiled gene expression changes upon lncRNA knockdown in breast cancer. We identified four microarray datasets that permitted our interrogation of genes regulated by lncRNAs LincK, LincIN, SPRY4-IT1 and AC009283.1. We specifically analysed changes in miRNA transcripts within these datasets to study miRNAs regulated by each of the four lncRNAs. We subsequently identified the predicted mRNA targets for these miRNAs to uncover possible lncRNA/miRNA/mRNAs axes in breast cancer. These axes may be candidates for future investigation of gene regulation in breast cancer.

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.

The COVID-19 pandemic has caused the need for prioritization strategies for breast cancer treatment, where patients with aggressive disease, such as triple-negative breast cancer (TNBC) are a high priority for clinical intervention. In this review, we summarize how COVID-19 has thus far impacted the management of TNBC and highlighted where more information is needed to hone shifting guidelines. Due to the immunocompromised state of most TNBC patients receiving treatment, TNBC management during the pandemic presents challenges beyond the constraints of overburdened healthcare systems. We conducted a literature search of treatment recommendations for both primary and targeted TNBC therapeutic strategies during the COVID-19 outbreak and noted changes to treatment timing and drugs of choice. Further, given that SARS-CoV-2 is a respiratory virus, which has systemic consequences, management of TNBC patients with metastatic versus localized disease has additional considerations during the COVID-19 pandemic. Published dataset gene expression analysis of critical SARS-CoV-2 cell entry proteins in TNBCs suggests that the virus could in theory infect metastasized TNBC cells it contacts. This may have unforeseen consequences in terms of both the dynamics of the resulting acute viral infection and the progression of the chronic metastatic disease. Undoubtedly, the results thus far suggest that more research is required to attain a full understanding of the direct and indirect clinical impacts of COVID-19 on TNBC patients.

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