The Epigenetic Adaptation of ER+ Breast Cancer Cells to the Bone Microenvironment
Abstract
The spread of breast cancer cells from primary tumors may have already occurred at the time of diagnosis. The disseminated tumor cells (DTCs) and micrometastases survive in distant organs for years to decades before resuming aggressive growth. This is a prominent clinical challenge especially for estrogen receptor positive (ER+) breast cancer, of which risk of recurrence may last for decades. Adjuvant endocrine therapies have been applied systemically to eliminate the undetectable metastatic seeds. Although they significantly improve the overall survival, about 20%-40% of patients still develop distant metastases and most often to the bone as the first site. The recurrent tumors, although in most cases remain ER+ and responsive to endocrine therapies, tend to develop therapeutic resistance more rapidly as compared to primary tumors. Thus, how to overcome therapeutic resistance and eradicate these metastatic seeds is imperative for the ending of breast cancer. Unfortunately, there is currently no biomarker to predict risk of recurrence for ER+ breast tumors beyond 5 years after surgery, suggesting that the biological and therapeutic properties of metastatic seeds may significantly deviate from those of primary tumors. This deviation may result from an independent evolution process and/or interactions with the microenvironment of distant organs such as bone. In either case, it is critical to investigate the metastatic seeds in a relevant microenvironment. In our previous Breast Cancer Research Program-funded research, we have developed a series of preclinical platforms and technologies to examine the biological properties and therapeutic responses of microscopic metastases at a single-cell level. These platforms and technologies allow us to study ER+ breast cancer cells in the bone microenvironment for the first time in the field. We discovered that micrometastases in the bone predominantly localize in specific sites where new bone is being generated, which we named “the osteogenic niche.” Surprisingly, when we interrogated the ER signaling in these micrometastases, we found that they have almost become ER- cells and responded very poorly to adjuvant endocrine therapies. This loss of ER expression is transient – it is recovered after bone metastases further progress into a more advanced and diagnosable stage. We further revealed several molecular pathways that cause the ER downregulation and others that might result from the downregulation. Importantly, these global changes induced by the bone microenvironment do not appear to be solely through Darwinian selection, i.e., selection of a subset of cancer cells that pre-exist, but also by alteration of chromatin structures of cancer cells, a process referred to as “epigenomic reprogramming.” This latter effect profoundly changes the status of cancer cells toward stem cells, which presumably cause resistance to therapies and facilitate further dissemination to other organs. Herein, we propose to target the discovered pathways to reverse the effects of microenvironment and restore sensitivity to endocrine therapies. Fortunately, several drugs are already developed to target these pathways in other cancer types, which will accelerate future translation for metastatic breast cancer. Specifically, we aim to (1) further investigate mechanisms underlying the microenvironment-induced endocrine resistance with focuses on identifying the most suitable therapeutic targets and the temporal window of therapeutic intervention, and (2) characterize the toxicity profiles of the drugs in combination and on top of standard-of-care (their individual safety is already proven in Phase I clinical trials), and carry out proof-of-concept preclinical experiments to establish the optimal therapeutic strategies to prevent and/or cure bone metastases. Although our experimental plan focuses on bone metastases, we are not ignoring the fact that other metastases also need to be preve
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010375
Entities
People
- Xiang Zhang
Organizations
- Baylor College of Medicine
- United States Army