Targeting Cox-2 And Rank In Aggressive Breast Cancers: Inflammatory Breast Cancer And Triple-Negative Breast Cancer

Author

Monica E. Reyes, The University of Texas Graduate School of Biomedical Sciences at HoustonFollow

Date of Graduation

12-2014

Document Type

Dissertation (PhD)

Program Affiliation

Cancer Biology

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Naoto T. Ueno, M.D., Ph.D.

Committee Member

Oliver Bogler, Ph.D.

Committee Member

Joya Chandra, Ph.D.

Committee Member

James M. Reuben, Ph.D.

Committee Member

Bedrich L. Eckhardt, Ph.D.

Abstract

Inflammatory breast cancer (IBC) and triple-negative breast cancer (TNBC) are two highly aggressive breast cancer subtypes associated with a poor outcome. Despite sensitivity to current treatment, these breast cancers subtypes have a high recurrence rate and proclivity to metastasize early. The aggressiveness of IBC and TNBC have been linked to CSCs and epithelial to mesenchymal transition (EMT), which are critical features of breast cancer progression and metastasis. The clinical challenge faced in the treatment of IBC and TNBC is finding a treatment strategy to target the cancer stem-like (CSC) population to block metastasis. Cyclooxygenase-2 (COX-2) and receptor activator of nuclear factor kappa B ligand/receptor activator of nuclear factor kappa B (RANKL/RANK) pathway mediate an inflammatory response linked to breast cancer progression. However, the mechanism of how COX-2 and RANKL/RANK regulates the progression of IBC and TNBC, respectively, is unclear. Therefore, we investigated COX-2 and RANKL/RANK in IBC and TNBC. We hypothesize that targeted inhibition of COX-2 and RANK in IBC and TNBC, respectively, could eradicate CSCs to suppress tumor progression.

We observed elevated COX-2 levels in EGFR-positive IBC cells and a significant correlation between COX-2 and EGFR gene expression in IBC tumors. How COX-2 linked to CSCs and regulates IBC progression is not well understood. We hypothesize COX-2 to be critical for IBC progression through regulation of the CSC population. Celecoxib, a selective COX-2 inhibitor, has anti-tumorigenic effects by reducing breast cancer cell migration and invasion. Celecoxib treatment in an IBC xenograft mouse model reversed EMT and downregulated expression of the embryonic stem cell regulator Nodal. We concluded COX-2 regulation of the CSCs through Nodal contributed to the progression of IBC and targeting the COX-2 has clinical relevance in blocking the progression of IBC.

RANKL/RANK pathway promotes the invasion, EMT and mammary epithelial stem cell population. We observed elevated expression in TNBC tumors and RANKL to be an independent prognostic factor for worse outcome in RANK-positive TNBC patients. How RANK promotes TNBC progression is not clear. We hypothesize that suppression of RANK inhibits TNBC progression through eradication of CSCs. We observed the suppression of RANK to reduce MDA-MB-231 cell migration and invasion, and mammosphere formation. Stem cell genes, implicated in inflammatory signaling, were down-regulated in MDA-MB-231 RANK shRNA cells.

Collectively, our findings suggest COX-2 and RANK to regulate of CSCs in IBC and TNBC potentially through mediating an inflammatory response. Future pre-clinical studies are needed to further interrogate COX-2 and RANK as novel therapeutic targets for IBC and TNBC.

Keywords

EGFR, COX-2, Nodal, RANK, RANKL, NF-kappa B, triple-negative, inflammatory, breast cancer, celecoxib, denosumab