Estrogen controls mTOR signaling and mitochondrial function via WNT4 in lobular carcinoma

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, yet signaling mediated by WNT4 is poorly understood. We utilized reverse phase protein array (RPPA) to characterize ER and WNT4-driven signaling in ILC cells, and identified WNT4 as a mediator of downstream mTOR signaling via p70-S6K. Independent of mTOR/p70-S6K, ER and WNT4 control levels of MCL-1, which is associated with mitochondrial function. In this context, knockdown of WNT4 caused accumulation of reactive oxygen species and decreased ATP production that precede cell death. WNT4 regulation of both mTOR signaling and MCL-1 levels was also observed in anti-estrogen resistant models of ILC. Further, we identified that high WNT4 expression is associated with similar mTOR pathway activation in serous ovarian cancer tumors, suggesting that this WNT4 pathway is important in multiple tumor types. The identified downstream pathways represent potential targets to inhibit WNT4 signaling in ovarian cancer and overcome anti-estrogen resistance for patients with ILC.