| Autor: |
Shackleford MT; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Rao DM; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Bordeaux EK; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Hicks HM; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Towers CG; Department of Pharmacology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Sottnik JL; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA., Oesterreich S; Women's Cancer Research Center, Dept. of Pharmacology & Chemical Biology, UPMC Hillman Cancer Center, Pittsburgh, PA 15232, USA., Sikora MJ; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA. |
| Abstrakt: |
Invasive lobular carcinoma of the breast (ILC) is strongly estrogen-driven and represents a unique context for estrogen receptor (ER) signaling. In ILC, ER controls the expression of the Wnt ligand WNT4, which is critical for endocrine response and anti-estrogen resistance. However, signaling mediated by WNT4 is cell type- and tissue-specific, and has not been explored in ILC. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells and identified that WNT4 mediates downstream mTOR signaling via phosphorylation of S6 Kinase. Additionally, ER and WNT4 control levels of MCL-1, which is associated with regulation of mitochondrial function. In this context, WNT4 knockdown led to decreased ATP production and increased mitochondrial fragmentation. WNT4 regulation of both mTOR signaling and MCL-1 were also observed in anti-estrogen resistant models of ILC. We identified that high WNT4 expression is associated with similar mTOR pathway activation in ILC and serous ovarian cancer tumors, suggesting that WNT4 signaling is active in multiple tumor types. The identified downstream pathways offer insight into WNT4 signaling and represent potential targets to overcome anti-estrogen resistance for patients with ILC. |
