an-ex-vivo-brain-slice-model-to-study-target-breast-cancer-brain

An <em>Ex Vivo</em> Brain Slice Model to Study and Target Breast Cancer Brain Metastatic Tumor Growth

Brain metastasis is a serious consequence of breast cancer for women as these tumors are difficult to treat and are associated with poor clinical ...

Drexel University College of Medicine

Hypoxic cancer cells have been shown to be more resistant to radiation therapy than normoxic cells. Hence, this study investigated whether ultrasound (US)-induced rupture of oxygen-carrying microbubbles (MBs) would enhance the response of breast cancer metastases to radiation.

Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model.

Altered metabolism and deregulated cellular energetics are now considered a hallmark of all cancers. Glucose, glutamine, fatty acids, and amino acids are the primary drivers of tumor growth and act as substrates for the hexosamine biosynthetic pathway (HBP). The HBP culminates in the production of an amino sugar uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) that, along with other charged nucleotide sugars, serves as the basis for biosynthesis of glycoproteins and other glycoconjugates. These nutrient-driven post-translational modifications are highly altered in cancer and regulate protein functions in various cancer-associated processes. In this review, we discuss recent progress in understanding the mechanistic relationship between the HBP and cancer.

Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer.

Breast tumors are heterogeneous and composed of different subpopulation of cells, each with dynamic roles that can change with stage, site, and microenvironment. Cellular heterogeneity is, in part, due to cancer stem-like cells (CSC) that share properties with stem cells and are associated with treatment resistance. CSCs rewire metabolism to meet energy demands of increased growth and biosynthesis. O-GlcNAc transferase enzyme (OGT) uses UDP-GlcNAc as a substrate for adding O-GlcNAc moieties to nuclear and cytoplasmic proteins. OGT/O-GlcNAc levels are elevated in multiple cancers and reducing OGT in cancer cells blocks tumor growth. Here, we report that breast CSCs enriched in mammosphere cultures contain elevated OGT/O-GlcNAcylation. Inhibition of OGT genetically or pharmacologically reduced mammosphere forming efficiency, the CD44/CD24, NANOG+, and ALDH+ CSC population in breast cancer cells. Conversely, breast cancer cells overexpressing OGT increased mammosphere formation, CSC populations , and also increased tumor initiation and CSC frequency . Furthermore, OGT regulates expression of a number of epithelial-to-mesenchymal transition and CSC markers including CD44, NANOG, and c-Myc. In addition, we identify Krüppel-like factor 8 (KLF8) as a novel regulator of breast cancer mammosphere formation and a critical target of OGT in regulating CSCs. IMPLICATIONS: These findings demonstrate that OGT plays a key role in the regulation of breast CSCs  and tumor initiation , in part, via regulation of KLF8, and thus inhibition of OGT may serve as a therapeutic strategy to regulate tumor-initiating activity.

Article	Year
Breast Cancer Brain Metastasis Response to Radiation After Microbubble Oxygen Delivery in a Murine Model. Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine\| PubMed ID: 31124171	2019
Fueling the fire: emerging role of the hexosamine biosynthetic pathway in cancer. BMC biology\| PubMed ID: 31272438	2019
O-GlcNAc Transferase Regulates Cancer Stem-like Potential of Breast Cancer Cells. Molecular cancer research : MCR\| PubMed ID: 31974291	2020

Lorela Ciraku

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