Systemic Glucocorticoid Signaling Induced by Breast Cancer Cell Derived Extracellular Vesicles

PROJECT SUMMARY Despite the wide use of glucocorticoids to manage symptoms in people with solid tumors, these steroids have been linked to tumor progression and metastasis especially in breast cancers that are negative for estrogen receptor. Here we will investigate how extracellular vesicles produced by breast cancer cells cause an overproduction of glucocorticoids, the “stress hormones”, and how this affects normal cells in the body to facilitate breast cancer metastasis. The goals of this study are: (1) to identify the mechanism by which cancer cell-produced extracellular vesicles enhance glucocorticoid production; (2) to determine the effect of activated glucocorticoid signaling at the whole body level; and (3) to explore the use of clinically available pharmacological inhibitors of glucocorticoids in cancer treatment. In Aim 1, we will determine the mechanism(s) through which extracellular vesicles from breast cancer cells lead to an overactivation of the neural control pathway that is responsible for the production of glucocorticoids. We will focus on pre-selected microRNAs in the extracellular vesicles for their role in regulating this central control pathway. In Aim 2, we will determine the gene regulatory effects of glucocorticoid signaling that is induced at the whole body level. We will focus on the functional role of those genes involved in the formation of pre- metastatic niches especially in the lungs, and will dissect the immunomodulatory and non-immune effects of cancer-induced glucocorticoid signaling. In Aim 3, we will evaluate the anti-tumor and anti-metastasis effects of clinically approved adrenal steroidogenesis inhibitors and glucocorticoid receptor antagonists, either as monotherapy or in combination with a first-line treatment for breast cancer. Next, we will compare levels of selected markers in the blood of breast cancer patients and non-cancer controls, as well as the associations of these blood markers with indicators of glucocorticoid signaling in tumor tissues. The proposed project will provide a new understanding of the dynamic and reciprocal communication between cancer and host at the whole body level. We will establish the mechanisms through which tumor-derived factors, such as extracellular vesicles, directly influence the neuroendocrine pathway that controls glucocorticoid production, and will develop a high-resolution map for the tissue-specific and cell type-specific target genes regulated by glucocorticoids. Results from this project may establish clinical evidence for the investigated mechanisms and explore if we may select breast cancer patients who will benefit from adding an anti-glucocorticoid therapy to their anticancer treatment.