Awakening of Dormant Breast Cancer Cells in the Bone Marrow

Simple Summary: Breast cancer cells travel via the bloodstream to the bone before the cancer is detectable in the breast. These disseminated cells are resistant to adjuvant chemotherapy and hormone therapy administered for the very purpose of eliminating them. They recur steadily for more than 20 years, resulting in incurable diseases. The bone marrow location, or niche, which normally provides a nest for blood-forming cells to enable them to generate blood for the entire lifetime of an individual, also protects these disseminated tumor cells and places them into a state of quiescence called dormancy. Dormant cancer cells can wake up from stimulation by life events, including a gradual increase in bone marrow fat cells and loss of estrogen with aging, inflammation, new blood vessel formation, trauma, surgery, abnormal blood clotting conditions, anxiety and depression. Many investigations have tested ways of killing disseminated cells or keeping them dormant, and some have entered clinical trials. Up to 40% of patients with breast cancer (BC) have metastatic cells in the bone marrow (BM) at the initial diagnosis of localized disease. Despite definitive systemic adjuvant therapy, these cells survive in the BM microenvironment, enter a dormant state and recur stochastically for more than 20 years. Once they begin to proliferate, recurrent macrometastases are not curable, and patients generally succumb to their disease. Many potential mechanisms for initiating recurrence have been proposed, but no definitive predictive data have been generated. This manuscript reviews the proposed mechanisms that maintain BC cell dormancy in the BM microenvironment and discusses the data supporting specific mechanisms for recurrence. It addresses the well-described mechanisms of secretory senescence, inflammation, aging, adipogenic BM conversion, autophagy, systemic effects of trauma and surgery, sympathetic signaling, transient angiogenic bursts, hypercoagulable states, osteoclast activation, and epigenetic modifications of dormant cells. This review addresses proposed approaches for either eliminating micrometastases or maintaining a dormant state.