The Prostaglandin E2 Pathway and Breast Cancer Stem Cells: Evidence of Increased Signaling and Potential Targeting

Abstract

Culprits of cancer development, metastasis, and drug resistance, cancer stem cells (CSCs) are characterized by specific markers, active developmental signaling pathways, metabolic plasticity, increased motility, invasiveness, and epithelial-mesenchymal transition. In breast cancer, these cells are often more prominent in aggressive disease, are amplified in drug-resistant tumors, and contribute to recurrence. For breast cancer, two distinct CSC populations exist and are typically defined by CD44+/CD24- cell surface marker expression or increased aldehyde dehydrogenase (ALDH) activity. These CSC populations share many of the same properties but also exhibit signaling pathways that are more active in CD44+/CD24- or ALDH+ populations. Understanding these CSC populations and their shared or specific signaling pathways may lead to the development of novel therapeutic strategies that will improve breast cancer patient outcomes. Herein, we review the current evidence and assess published patient tumor datasets of sorted breast CSC populations for evidence of heightened prostaglandin E2 (PGE2) signaling and activity in these breast CSC populations. PGE2 is a biologically active lipid mediator and in cancer PGE2 promotes tumor progression and poor patient prognosis. Overall, the data suggests that PGE2 signaling is important in propagating breast CSCs by enhancing inherent tumor-initiating capacities. Development of anti-PGE2 signaling therapeutics may be beneficial in inhibiting tumor growth and limiting breast CSC populations.

Combined Gadolinium and Boron Neutron Capture Therapies for Eradication of Head-and-Neck Tumor Using Gd10B6 Nanoparticles under MRI/CT Image Guidance

“…It is well documented that elevated levels of TGF-α and p53 in H&N tumors are highly associated with tumor growth and recurrence. − Cancer stem cells (CSCs, also known as tumor-initiating cells) play a key role in tumor growth, recurrence, metastasis, and chemodrug resistance. , CD44 is a specific CSCs’ membrane surface biomarker and has been involved in promotion of tumor growth and metastasis. , Prostaglandin E 2 (PGE 2 ) is the most abundant prostaglandin found in various human malignant tumors. Binding of PGE 2 to the EP2 and EP4 receptors on the cancer cell membrane will trigger secretion of cytokines to promote cancer cells’ growth, proliferation, agiogenesis, metastasis, as well as suppression of host antitumor immunity. − Therefore, a high level of PGE 2 is directly associated with a high probability of tumor recurrence. In addition, hypoxia-inducible factor-α (HIF-α) is the main transcription factor determining the cellular response to hypoxia tumor domains.…”

Oncolytic Adenovirus for the Targeting of Paclitaxel-Resistant Breast Cancer Stem Cells

“…This intriguing observation may potentially be linked to increased Cox-2 activity in the BCSC populations compared to other breast cancer cells. Although direct evidence is lacking, it is known that BCSCs exhibit heightened NF-kB pathway activity and prostaglandin expression [ 86 ]. Cox-2 expression is regulated by the NF-kB pathway, the effectors of which are often overexpressed in breast cancer cells [ 87 ], and Cox-2 in turn regulates prostaglandin levels, which play a crucial role in tumor growth regulation [ 88 ].…”

Interferon-gamma is Quintessential for NOS2 and COX2 Expression in ER-Breast Tumors that Lead to Poor Outcome

“…Elongation and EMT induced by NO are known to mediate these effects (16). Also, IL1 and PGE2 enhance EMT and cell motility in breast cancer (37,38). Herein, IFNg and ILb1/TNFa promote motility and elongation (7).…”