Triple negative breast cancer: approved treatment options and their mechanisms of action.

PURPOSE: Breast cancer, the most prevalent cancer worldwide, consists of 4 main subtypes, namely, Luminal A, Luminal B, HER2-positive, and Triple-negative breast cancer (TNBC). Triple-negative breast tumors, which do not express estrogen, progesterone, and HER2 receptors, account for approximately 15-20% of breast cancer cases. The lack of traditional receptor targets contributes to the heterogenous, aggressive, and refractory nature of these tumors, resulting in limited therapeutic strategies. METHODS: Chemotherapeutics such as taxanes and anthracyclines have been the traditional go to treatment regimens for TNBC patients. Paclitaxel, docetaxel, doxorubicin, and epirubicin have been longstanding, Food and Drug Administration (FDA)-approved therapies against TNBC. Additionally, the FDA approved PARP inhibitors such as olaparib and atezolizumab to be used in combination with chemotherapies, primarily to improve their efficiency and reduce adverse patient outcomes. The immunotherapeutic Keytruda was the latest addition to the FDA-approved list of drugs used to treat TNBC. RESULTS: The following review aims to elucidate current FDA-approved therapeutics and their mechanisms of action, shedding a light on the various strategies currently used to circumvent the treatment-resistant nature of TNBC cases. CONCLUSION: The recent approval and use of therapies such as Trodelvy, olaparib and Keytruda has its roots in the development of an understanding of signaling pathways that drive tumour growth. In the future, the emergence of novel drug delivery methods may help increase the efficiency of these therapies whiel also reducing adverse side effects.

BRK confers tamoxifen-resistance in breast cancer via regulation of tyrosine phosphorylation of CDK1.

Tamoxifen (Tam) has been the first-line therapy for estrogen receptor-positive breast cancer since its FDA-approval in 1998. Tam-resistance, however, presents a challenge and the mechanisms that drive it have yet to be fully elucidated. The non-receptor tyrosine kinase BRK/PTK6 is a promising candidate as previous research has shown that BRK knockdown resensitizes Tam-resistant breast cancer cells to the drug. However, the specific mechanisms that drive its importance to resistance remain to be investigated. Here, we investigate the role and mechanism of action of BRK in Tam-resistant (TamR), ER+, and T47D breast cancer cells using phosphopeptide enrichment and high throughput phopshoproteomics analysis. We conducted BRK-specific shRNA knockdown in TamR T47D cells and compared phosphopeptides identified in these cells with their Tam-resistant counterpart and parental, Tam-sensitive cells (Par). A total of 6492 STY phosphosites were identified. Of these sites, 3739 high-confidence pST sites and 118 high-confidence pY sites were analyzed for significant changes in phosphorylation levels to identify pathways that were differentially regulated in TamR versus Par and to investigate changes in these pathways when BRK is knocked down in TamR. We observed and validated increased CDK1 phosphorylation at Y15 in TamR cells compared to BRK-depleted TamR cells. Our data suggest that BRK is a potential Y15-directed CDK1 regulatory kinase in Tam-resistant breast cancer.

Smart and low-cost fluorometer for identifying breast cancer malignancy based on lipid droplets accumulation.

The most common cause of breast cancer-related death is tumor recurrence. To develop more effective treatments, the identification of cancer cell specific malignancy indicators is therefore critical. Lipid droplets are known as an emerging hallmark in aggressive breast tumors. A common technique that can be used for observing molecules in cancer microenvironment is fluorescence microscopy. We describe the design, development and applicability of a smart fluorometer to detect lipid droplet accumulation based on the emitted fluorescence signals from highly malignant (MDA-MB-231) and mildly malignant (MCF7) breast cancer cell lines, that are stained with BODIPY dye. This device uses a visible-range light source as an excitation source and a spectral sensor as the detector. A commercial imaging system was used to examine the fluorescent cancer cell lines before being validated in a preclinical setting with the developed prototype. The outcomes indicate that this low-cost fluorometer can effectively detect the alterations levels of lipid droplets and hence distinguish between "moderately malignant" and "highly malignant" cancer cells. In comparison to prior research that used fluorescence spectroscopy techniques to detect cancer biomarkers, this study revealed enhanced capability in classifying mildly and highly malignant cancer cell lines.