The American Cancer Society recently revealed the sobering fact that every 2.3 minutes one woman is diagnosed with breast cancer and every 13 minutes one woman dies of breast cancer in the U.S. alone. To reduce the burden of breast cancer, and ultimately, reduce breast cancer death, we urgently need to develop more effective prevention and early intervention strategies. Although chemoprevention trials of anti-estrogenic tamoxifen (Tam) and raloxifene have shown an encouraging 42% decrease in estrogen receptor positive (ER+) breast cancer incidence, there is no effective agent for prevention of ER negative (ER-) breast cancer. To develop effective prevention strategies for ER- breast cancer, we need to identify key alterations driving ER- lesion initiation and progression and target them with low-toxicity agents for prevention. To surmount this challenge, we have performed an unbiased reverse phase protein array (RPPA) analysis on fine needle aspiration biopsies of women with high grade Tam-resistant (TamR) atypia and identified p70S6K hyper activation as a major signaling alteration in TamR atypia compared to Tam-sensitive atypia. Consistently, gene set enrichment analysis (GSEA) revealed that Akt/p70S6K-activated genes are highly enriched as early as in ADH compared to paired normal tissue from breast cancer patients. In addition, we also detected p70S6K overexpression and hyper phosphorylation in atypia lesions of a transgenic mouse model of ER- breast cancer (MMTV-neu/NDL2-5) compared to the mammary glands (MGD) of wild type mice; we observed the same phenomenon in MCF10DCIS, an early stage triple negative breast cancer (TNBC) model, compared to non- transformed mammary epithelial cells (MECs). p70S6K activation dysregulates multiple biological functions, e.g., increasing HIF-1a, a master regulator of hypoxic responses and cellular metabolism. Indeed, we found that p70S6K-activated and ER- MECs had increased HIF-1a and glycolysis which are diminished by p70S6K inhibitor treatment. These led us to hypothesize that p70S6K activation in MECs and in mammary atypia can drive initiation and progression of ER- breast cancer by metabolic dysregulation, and that p70S6K-targeting agents combined with dietary/metabolic modulation may prevent ER- breast cancer. To test this hypothesis, we will 1) determine the functional roles of p70S6K activation in MEC early transformation and atypia transition to ER- breast cancer; 2) dissect the molecular mechanisms of p70S6K-driven MEC transformation and ER- atypia progression; and 3) explore the potential of targeting p70S6K by using low doses of low-toxicity inhibitors, in combination with dietary/metabolic modulation, for chemo-dietary prevention/early intervention in ER- mammary tumor animal models. The successful completion of the proposed studies will bring i) new understanding of ER- breast cancer initiation, and ii) effective prevention/intervention strategies for ER- breast cancer. Our research findings could be readily translated into clinical trials as a novel prevention strategy for high risk women and, ultimately, reduce breast cancer-related death.
This R01 application tackles one of the most challenging problems in the cancer field: there is no effective prevention strategy for women with estrogen receptor negative (ER-) breast cancer due to lack of basic understanding of the disease. The goal of this research is to determine (i) whether p70S6K activation plays a critical role in ER- breast cancer initiation, and (ii) the potential of targeting p70S6K, in combination with dietary/metabolic modulations, for prevention of ER- breast cancer. Successful completion of this research will allow rapid translation to clinical trials for prevention of ER- breast cancer i high-risk women, which will significantly further reduce breast cancer mortality in long-term.
