Breast cancer dormancy: need for clinically relevant models to address current gaps in knowledge

Abstract

Breast cancer is the most commonly diagnosed cancer in the USA. Although advances in treatment over the past several decades have significantly improved the outlook for this disease, most women who are diagnosed with estrogen receptor positive disease remain at risk of metastatic relapse for the remainder of their life. The cellular source of late relapse in these patients is thought to be disseminated tumor cells that reactivate after a long period of dormancy. The biology of these dormant cells and their natural history over a patient's lifetime is largely unclear. We posit that research on tumor dormancy has been significantly limited by the lack of clinically relevant models. This review will discuss existing dormancy models, gaps in biological understanding, and propose criteria for future models to enhance their clinical relevance.

Fig. 1. Breast cancer recurrence.

Breast cancer recurrence is dependent on (a) disease subtype and (b) stage at diagnosis. a Is reproduced under open access Crown Copyright Oxford University Press from Fig. 2E of Copson et al. 2013. b Is reproduced with permission from RightsLink from Fig. 2B of Pan et al. 2017³.

Fig. 2. Schematic representation of a metabolic regulatory network simulator.

The simulator couples key redox-sensing proteins (HIF-1, AMPK, MYC) with main metabolic pathways (glucose, glutamine, and fatty acid). Gray solid arrows represent positive regulations and gray bar-headed arrows represent negative regulations. Pathways labeled in red are up-regulated and those in blue are down-regulated. The transition from M-BCSC to E-BCSC and the reverse can be induced by alteration of cellular ROS levels. The simulator can be adapted to incorporate additional features to study, for example, the effects of inhibiting antioxidant factors. pMET: partial MET (mesenchymal-epithelial transition, the reverse of EMT); pEMT: partial EMT; mtROS: mitochondrial reactive oxygen species; noxROS: NADPH oxidase-derived reactive oxygen species; GSH: glutathione. This figure is adapted from Jia et al. 2019.

Fig. 3. Cellular dormancy in the bone marrow niche.

Schematic representation of perivascular, hematopoietic, and endosteal bone marrow niches. It is not well established in humans what niche the tumor cells occupy while in the dormant state. In the proliferative state, bone metastasis is associated with the cycle of bone resorption that occurs in the endosteal niche.

Fig. 4. Schematic representation of in vitro models of dormancy that increase complexity of geometric and cellular components.

Engineered 3D models generally exhibit the greatest geometric and cellular complexity combining both multicellular models and engineered 3D geometry.

Fig. 5. Proposed integration of subfields of breast cancer dormancy research moving forward.

The successful study of breast cancer dormancy relies on the interplay between in vivo models of dormancy, in vitro manipulation, and patient samples in order to identify mechanisms of dormancy, generate new hypotheses, and develop therapies with the ultimate goal of new clinical trials to study breast cancer dormancy and to assess treatments.