Breast cancer survival rates vary according to stage, tumor grade, and receptor status. While some cancer patients respond well to targeted therapy many patients respond poorly. Critical for advancing new therapies is developing a better understanding of the molecular drivers of breast cancer tumorigenesis and malignant progression. The synthesis of new proteins (translation) is important for cancer cell survival, growth, and proliferation. eIF4E is a rate limiting step in translation. Targeting translation has been suggested as a novel strategy for therapy of malignancies originating in the epithelium since eIF4E regulates the translation of multiple malignancy associated mRNAs. eIF4E is activated by phosphorylation downstream of the Mnk 1 and 2 kinases. We hypothesized that phosphorylation of eIF4E plays a critical role in driving breast cancer and is elevated in advanced cancers and metastases. Using immunochemistry and semi-quantitative cellular pathology approaches we analyzed expression of eIF4E and phospho-eIF4E in 168 FFPE archived surgical specimens of normal breast, benign breast disease and pre-invasive, invasive, and metastatic breast cancer. Immunohistochemical stain in the cytoplasm and nuclei of breast epithelial cells was evaluated microscopically by the area of epithelium stained and the intensity of stain (Histoscore = Area X Intensity). We found that expression of eIF4E in the cytoplasm and nuclei of breast epithelial cells was highly correlated with tumor progression (p < 0.0001 and p = 0.0025, respectively). Similarly phospho-eIF4E expression increased in concert with tumor progression (p < 0.0001) in both the cytoplasm and nuclei of breast epithelial cells. Interestingly, while expression of both eIF4E and phospho-eIF4E was not significantly increased in benign breast disease, expression of both eIF4E and phospho-eIF4E was significantly increased in atypical duct hyperplasia (p = 0.01) and in carcinoma in situ (p < 0.0001) as well as in invasive ductal carcinoma (p < 0.0001) relative to normal duct epithelium. Expression of eIF4E and phospho-eIF4E was also increased in lobular carcinoma in situ relative to expression in normal lobules. Breast cancers of all receptor types (ER+/-, PR +/-, Her2+/-, and triple negative) had increased expression of eIF4E and phospho-eIF4E relative to normal duct epithelium. These data are consistent with the conclusion that eIF4E and phospho-eIF4E are critical factors in breast cancer development and progression and that targeting either eIF4E or phosphorylation of eIF4E may be an effective strategy for therapy of all subtypes of breast cancer.
Citation Format: Chad A. Dumstorf, Larry E. Douglass, James A. Deddens, Thomas G. Lewis, Kyle Darpel, Christian Gausvik, Jeremy R. Graff, Julia H. Carter. Phosphorylation of eIF4E is a critical factor in development and progression of breast cancer in women. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3919.