Estrogen receptor alpha and p90 ribosomal s6 kinase in homeostasis and disease
The American Cancer Society estimates that over 250,000 new cases of invasive breast cancer are diagnosed annually in the United States. Subtyping breast cancer and the identification of targeted therapies have greatly improved our ability to manage the disease. However, major clinical challenges still exist including resistance to therapy and metastasis. The majority of breast cancers are estrogen receptor alpha positive (ER+), indicating their hormone-responsive nature. These patients are treated with targeted therapies against estrogen signaling. Estrogen receptor alpha (ERalpha) is a ligand activated transcription factor that promotes cell proliferation in both the normal breast and ER+ breast cancer. Thus, understanding the processes underlying estrogen signaling homeostasis can improve the identification of novel therapies for ER+ breast cancer. The Ser/Thr kinase family, ribosomal S6 kinases (RSK1 - 4), has been implicated in the etiology of various human diseases, including breast cancer, cardiovascular disease, fibrosis, and others, yet there are no clinical RSK inhibitors. RSKs are downstream effectors of the mitogen-activated kinase kinase (MEK 1/2) – extracellular regulated kinase (ERK1/2) pathway. RSK is capable of phosphorylating both cytoplasmic and nuclear substrates involved in cell proliferation, survival, and motility. Despite the disrupted RSK activity in a variety of human diseases, the underlying mechanisms are poorly understood. While studying RSK2-knockout mice (RSK2-KO), we discovered a role for RSK2 in homeostasis of estrogen signaling (Figure 1.1). RSK2 has been implicated in ER+ breast cancer, however the role in normal mammary physiology was unknown. In chapter 2, we describe the identification of ERalpha regulation by ERK1/2 – RSK2 in normal mammary epithelial cells. We discovered that RSK2 is a negative regulator of normal ERalpha signaling, and RSK2-KO mammary ER+ cells have increased oxidative stress and DNA-damage. These findings have important implications for ER+ breast cancer and women taking exogenous estrogen therapies. In the second part of this thesis, we investigate targeting RSK2 signaling in cardiac pathophysiology and breast cancer. Based on reports that increased RSK activity is associated with human cardiovascular damage, we hypothesized that activation of RSK is also involved in adverse cardiovascular events of cancer chemotherapy. In chapter 3, we demonstrate the potential of a RSK inhibitor to prevent anthracycline chemotherapy-induced cardiac toxicity in vivo. This study confirms clinical reports of a pathological role for increased cardiac RSK activity. In chapter 4, we demonstrate that targeting RSK 1/2 in the aggressive, ER-negative, triple-negative breast cancer (TNBC) subtype can prevent the establishment and proliferation of metastasis. These preclinical proof of concept studies in chapters 3 and 4 suggest that targeting RSK is dual strategy in cancer, both reducing the side effects of chemotherapy and preventing cancer progression. To accompany these studies, we developed a novel RSK inhibitor, C5-npropyl-cyclitol SL0101 (C5”), with increased drug like properties. The synthesis and evaluation of C5” is described in chapters 5 – 8. Overall, these studies increase our understanding of RSK in homeostasis and pathophysiology.