Targeting Aberrant p70S6K Activation for Estrogen Receptor–Negative Breast Cancer Prevention

Abstract

The prevention of estrogen receptor negative (ER−) breast cancer remains a major challenge in the cancer prevention field although anti-estrogen and aromatase inhibitors (AIs) have shown adequate efficacy in preventing estrogen receptor positive (ER+) breast cancer. Lack of commonly expressed, druggable targets is a major obstacle for meeting this challenge. Previously, we detected the activation of Akt signaling pathway in atypical hyperplasic early stage lesions of patients. In the current study, we found that Akt and the downstream 70kDa ribosomal protein S6 kinase (p70S6K) signaling pathway was highly activated in ER− pre-malignant breast lesions and ER− breast cancer. Additionally, p70S6K activation induced transformation of ER− human mammary epithelial cells (hMECs). Therefore, we explored the potential of targeting Akt/p70S6K in the p70S6K activated, ER− hMECs models and mouse mammary tumor models for the prevention of ER− breast cancer. We found that a clinically applicable Akt/p70S6K dual inhibitor, LY2780301, drastically decreased proliferation of hMECs with ErbB2-induced p70S6K activation via Cyclin B1 inhibition and cell cycle blockade at G0–G1 phase, while it did not significantly reverse the abnormal acinar morphology of these hMECs. In addition, a brief treatment of LY2780301 in MMTV-neu mice that developed atypical hyperplasia (ADH) and mammary intraepithelial neoplasia (MIN) lesions with activated p70S6K was sufficient to suppress S6 phosphorylation and decrease cell proliferation in hyperplasic MECs. In summary, targeting the aberrant Akt/p70S6K activation in ER− hMEC models in vitro and in the MMTV-neu transgenic mouse model in vivo effectively inhibited Akt/S6K signaling and reduced proliferation of hMECs in vitro and ADH/MIN lesions in vivo, indicating its potential in prevention of p70S6K activated ER− breast cancer.

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“…The 70 kDa ribosomal protein S6 kinase (p70S6K) has contributed to the development of breast cancer (Miller et al, 2011). For instance, a study conducted with breast tissue biopsy from women with high grade of Tamoxifen resistance revealed high levels of Akt/p70S6K activation and confirmed that Akt/p70S6K signaling pathway was activated in early stage breast disease (Wang et al, 2017). In our study, the mixture of phenolics in CphE reduced p70S6K levels in 4T1 cells more effectively than quercetin alone.…”

Ribosome Proteins Represented by RPL27A Mark the Development and Metastasis of Triple-Negative Breast Cancer in Mouse and Human

“…To further confirm that, we checked the expression of the major component genes of EIF2 signaling and found upregulation of multiple genes, including EIF2AK1 (HRI protein coding gene), EIF2AK2 (PKR protein coding gene), EIF2AK4 (GCN2 protein coding gene), EIF2B5, and AKT2 ( Figure 7E ; Rios-Fuller et al, 2020 ). Other ingenuity canonical pathways included regulation of eIF4 and p70S6K signaling and mTOR signaling ( Figure 7D ), both of which were closely associated with TNBC biological activities ( Madden et al, 2014 ; Wang et al, 2017 ; Zagorac et al, 2018 ). Graphic regulatory networks integrating ingenuity canonical pathways and upstream regulators of the metastatic cells gave a core pathway of cell viability of breast cancer cells, which was closely related with EIF2 signaling and regulators of RB1, TP53, and MYC ( Figure 7F ).…”

When fats commit crimes: fatty acid metabolism, cancer stemness and therapeutic resistance

“…As the key rate-limiting enzyme of FAO, CPT1 conjugates fatty acids with carnitine for translocation into the mitochondria; therefore, it controls FAO directly and thus facilitates cancer metabolic reprogramming. CPT1 also shares multiple connections with many other cellular signaling pathways often dysregulated in cancers, such as aerobic glycolysis, FAS, p53/AMPK axis, mutated RAS, mTOR and STAT3 [ 91 , 92 ]. This evidence positions CPT1 as a multifunctional mediator in cancer pathogenesis and resistance to treatment.…”