Dormancy in breast cancer

Abstract

Tumor dormancy describes a prolonged quiescent state in which tumor cells are present, but disease progression is not yet clinically apparent. Breast cancer is especially known for long asymptomatic periods, up to 25 years, with no evidence of the disease, followed by a relapse. Factors that determine the cell's decision to enter a dormant state and that control its duration remain unclear. In recent years, considerable progress has been made in understanding how tumor cells circulating in the blood interact and extravasate into secondary sites and which factors might determine whether these cells survive, remain dormant, or become macrometastases. The mechanisms of tumor cell dormancy are still not clear. Two different hypotheses are currently discussed: tumor cells persist either by completely withdrawing from the cell cycle or by continuing to proliferate at a slow rate that is counterbalanced by cell death. Because dormant disseminated tumor cells may be the founders of metastasis, one hypothesis is that dormant tumor cells, or at least a fraction of them, share stem cell-like characteristics that may be responsible for their long half-lives and their suggested resistance to standard chemotherapy. Therefore, knowledge of the biology of tumor cell dormancy may be the basis from which to develop innovative targeted therapies to control or eliminate this tumor cell fraction. In this review, we discuss biological mechanisms and clinical implications of tumor dormancy in breast cancer patients.

Keywords: circulating tumor cell; disseminated tumor cell; targeted therapy; tumor dormancy.

Figure 1

Possible fates of tumor cells detached from primary tumor. Notes: Tumor cells disseminate at a secondary site and are subject to one of three possible fates: the tumor cells can proliferate aggressively, resulting in early metastasis; undergo apoptosis and die; or remain dormant. Two hypothetical models of tumor dormancy in breast cancer can occur: (1) in the single-cell dormancy model (left), cells derived from primary tumor remain quiescent in a state of G0–1 mitotic arrest at a secondary site and may be reactivated by genetic changes or by an altered microenvironment. (2) in the micrometastatic dormancy model (right), tumor cells proliferate and continue to form micrometastases at secondary homing sites. The micrometastases have a balanced state of proliferation and apoptosis; their growth is regulated by angiogenic and immunological factors within the microenvironment.