Altered Lipid Metabolism in Luminal Breast Cancer Stem Cells and Endocrine Resistance

点击翻译按钮获取中文摘要

Project Summary/Abstract: Over two thirds of newly diagnosed breast cancer patients have estrogen receptor (ER) and progesterone receptor (PR) positive or "luminal" breast cancer. Endocrine therapy is standard of care for these patients and frequently results in long-term disease-free survival or cure. However, one third of luminal breast cancer patients experience recurrence with metastatic and therapy-resistant disease. Recurrence is thought to arise from cancer stem cells (CSCs), a rare subpopulation of cancer cells within a tumor that exhibit stem-like characteristics. These include quiescence, metabolic flexibility, and resistance to endocrine and chemotherapies. These subpopulations are difficult to study in luminal breast cancers due to tumor heterogeneity that is not well understood and, while some tumors contain CD44+ cells, others lack such conventional CSC markers. Our lab has identified that a subpopulation of cytokeratin 5 (CK5)+ cells within luminal breast cancers contain CSC properties including resistance to endocrine and chemotherapies, and increased tumorsphere formation and tumor-initiation relative to CK5− cells. Additionally, we found that the CK5+ subpopulation expands with either progestin treatment or endocrine therapy such as tamoxifen (Tam) or estrogen withdrawal (EWD). CK5+ cells lose ER and PR expression and thus endocrine sensitivity. We used CK5 as a marker for luminal breast cancer CSCs to investigate unique CSC biology and to identify pharmacological targets to prevent disease recurrence for breast cancer patients. Lipidomic analysis of luminal breast cancer cells under EWD or that are Tam-resistant (TamR) revealed a significant loss of triglyceride analytes compared to control T47D cells. In addition, EWD and TamR cells lack visible lipid storage by ORO staining and fail to induce lipid droplet formation with progestins, as typically observed in PR+ luminal breast cancer cell lines. EWD and TamR T47D cells show decreased expression of de novo fatty acid synthesis enzymes, FASN and ACC1, compared to control cells suggesting the lipogenic phenotype typically observed in luminal breast cancer is lost in endocrine resistance. Together, I hypothesize that endocrine resistant luminal breast cancer cells recycle rather than store lipids and this is necessary to maintain CSC function. To test this, I plan on defining the mechanism by which endocrine resistant breast cancer cells shift lipids from storage in Aim 1 and assess the effect of lipid storage on luminal breast CSC function in Aim 2. Understanding CSC lipid biology in breast cancer endocrine resistance is a critical step in identifying therapeutic targets for recurrence prevention.