Today in breast cancer research, scientists are focused on determining the cause, risk, diagnostic testing options and treatment of this devastating disease. Of particular interest is identification of potential therapeutic targets that are known to contribute to the progression of breast cancer in order to develop treatments against these specific genes or proteins. This article review summarizes research completed by AlHossiny et al regarding the role of Ly6E/K signaling and TGF-beta is the progression of cancer, immune escape and subsequent drug resistance. Initial work by this group shed light on the role of mouse Ly6A in the regulation of TGF-beta, PTEN and the ERK/AKT signaling pathways to develop resistance to radiation and promote metastatic behavior of mammary tumors. Furthermore, heightened levels of mLy6A in tumor tissue correlated with a reduction of the novel tumor suppressor GDF10. With this information, AlHossiny set out to further elucidate the role of Ly6E in breast cancer malignancies and its potential to be a therapeutic target.
Ly6K was detected in immersion fixed paraffin-embedded sections of human lung cancer tissue using Sheep Anti-Human Ly6K Antigen Affinity-purified Polyclonal Antibody (Catalog # AF6648) at 3 µg/mL overnight at 4 °C. Before incubation with the primary antibody, tissue was subjected to heat-induced epitope retrieval using Antigen Retrieval Reagent-Basic (Catalog # CTS013). Tissue was stained using the Anti-Sheep HRP-DAB Cell & Tissue Staining Kit (brown; Catalog # CTS019) and counterstained with hematoxylin (blue). Specific staining was localized to cytoplasm and plasma membrane of cancer cells. View our protocol for Chromogenic IHC Staining of Paraffin-embedded Tissue Sections.
Ly6E/K, also known as murine Sca-1, is a stem cell antigen that’s expression has been associated with poor survival in patients with malignant tumors. Drug resistance and the protection of breast cancer tumors also hallmark Ly6E/K expression, yet its exact molecular mechanism is unknown. In order to better understand Ly6E/K, AlHossiny employed a wide range of experimental techniques in this article. To first establish the increased expression of Ly6K and Ly6E in breast cancer tissue, the online tool PROGgeneV2 was used to assess the gene expression microarray datasets. Next, the functional role of Ly6K was assessed using a Ly6K knockdown model in MDA-MB-231 TNBC cells. These cell samples were tested in western blot with a Ly6K primary antibody and showed reduced tumor cell colony formation and less tumor cell migration. Breast tissue samples were also tested with a Ly6K antibody alongside a Ly6E antibody and subsequently tested in qRT-PCR. Furthermore, the effect of Ly6K knockdown in MDA-MB-231 cells was examined in order to identify changes in gene expression with existing drug resistance targets and showed a reduction of ABCC3. ABCC3 is a known inducer of chemotherapeutic drug resistance.
In addition to confirming the role of Ly6E/K in malignant breast tissue, this article also revealed the potential pathway for Ly6E/K regulation. In essence, Ly6E is thought to regulate the tumor suppressor cytokine GDF10 and to distribute TGF-beta signaling by sequestering TGF-beta receptor 1. What’s more, Ly6E and Ly6K are both upregulated at the RNA level in human breast cancer tissue and are required for the formation of human breast cancer cells. This expression pattern and subsequent control over cancer cell is due in part to their ability to regulate TGF-beta and BMP signaling. This finding shows great promise for therapeutic treatments given the role of TGF-beta signaling in chemotherapy and drug resistance to begin with.
Overall, these findings suggest that Ly6K and Ly6E will be effective upstream thereapeutic targets involved in the signaling of TGF-beta in breast cancer progression.
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