Targeting Aberrant p70S6K Activation for Estrogen Receptor-Negative Breast Cancer Prevention
Preventing estrogen receptor-negative (ER-) breast cancer remains a significant challenge in the field of cancer prevention. While antiestrogens and aromatase inhibitors have proven effective for estrogen receptor-positive (ER+) breast cancer, ER- breast cancer lacks commonly expressed, druggable targets, posing a major obstacle. Previously, we observed activation of the Akt signaling pathway in early-stage atypical hyperplastic lesions in patients. In this study, we discovered that the Akt and downstream 70 kDa ribosomal protein S6 kinase (p70S6K) pathways were highly activated in ER- premalignant breast lesions and ER- breast cancers. Additionally, activation of p70S6K promoted the transformation of ER- human mammary epithelial cells (hMECs).
Given this, we investigated whether targeting the Akt/p70S6K pathway could prevent ER- breast cancer using p70S6K-activated ER- hMEC models and mouse mammary tumor models. Our findings showed that the dual Akt/p70S6K inhibitor LY2780301 significantly reduced proliferation of hMECs with ErbB2-induced p70S6K activation by inhibiting Cyclin B1 and inducing cell-cycle arrest at the G0-G1 phase. However, it did not markedly reverse abnormal acinar morphology in these cells. Moreover, short-term treatment with LY2780301 in MMTV-neu mice, which developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K, successfully suppressed S6 phosphorylation and reduced cell proliferation in hyperplastic MECs.
In conclusion, targeting the aberrant Akt/p70S6K activation in both ER- hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and decreased cell proliferation in vitro and in ADH/MIN lesions in vivo. These results suggest the potential of this approach for the prevention of p70S6K-activated ER- breast cancer.