Molecular Mechanisms Regulating Mouse Mammary Gland and Human Breast Tumor Cells

Division Of Basic Sciences - Nci

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Abstract

Cell-cell adhesion as a targetable property of metastatic cancer cells: Investigations of molecular events in Inflammatory Breast Cancer models including a 3D cell culture paradigm led to the discovery that that the COX-2/PGE2/ GSK3beta pathway promotes tumor cell adhesion by E-cadherin and is a candidate target for metastastic breast cancer. Inflammatory breast cancer (IBC) is an extremely aggressive subtype of breast cancer (BC; classified by NIH-GARD as Rare Disease) with pronounced racial and socioeconomic disparities. Clinical presentation includes extensive skin invasion and intralymphatic tumor cell emboli that exhibit E-cadherin (CDH1)-mediated cell-cell adhesions. The study of IBC thus offers an opportunity to understand the pathways leading to E-cadherin-associated metastasis. Through analysis of the C/EBPdelta (CEBPD) transcription factor, we found that prostaglandin-endoperoxide synthase 2 (COX-2, PTGS2) promoted E-cadherin-mediated adhesions, despite the reported role of COX-2 in epithelial-mesenchymal transition. Using an in vitro emboli formation assay, we found that COX-2, through activation of the serine-threonine kinase AKT/PKB and inhibition of GSK3beta, prevented proteasomal degradation of p120 catenin (CTNND1), which stabilizes E-cadherin cell adhesion complexes. Expression of E-cadherin and GSK3beta inhibition was confirmed in patient-derived xenografts (PDX) of metastatic breast cancers. Coexpression of E-cadherin and COX-2 was seen in breast cancer tissues from patients with poor outcome and, along with inhibitory GSK3beta phosphorylation, in patient-derived xenografts (PDX) including triple negative breast cancer (TNBC).Celecoxib alone decreased E-cadherin protein expression within xenograft tumors, though CDH1 mRNA levels increased, and reduced circulating tumor cell (CTC) clusters. In combination with paclitaxel, celecoxib attenuated or regressed lung metastases. This study has uncovered a mechanism by which metastatic breast cancer cells can maintain E-cadherin-mediated cell-to-cell adhesions and cell survival, suggesting that some patients with COX-2+/E-cadherin+ breast cancer may benefit from targeting of the PGE2 signaling pathway. Myeloid lineage response to tumor development: Ongoing work is analyzing the immune response to tumor cells in mice with a focus on the myeloid lineage. We discovered that CEBPD mediates several stages of neutrophil development and modulates neutrophil activities in the cancer context.