Breast Cancer Dormancy in Bone

Abstract

Purpose of review: The goal of this review is to summarize recent experimental and clinical evidence for metastatic latency and the molecular mechanisms that regulate tumor dormancy in the bone.

Recent findings: Tumor dormancy contributes to the progression of metastasis and thus has significant clinical implications for prognosis and treatment. Tumor-intrinsic signaling and specialized bone marrow niches play a pivotal role in determining the dormancy status of bone disseminated tumor cells. Experimental models have provided significant insight into the effects of the bone microenvironment on tumor cells; however, these models remain limited in their ability to study dormancy. Despite recent advances in the mechanistic understanding of how tumor cells remain dormant in the bone for prolonged periods of time, the signals that trigger spontaneous dormancy escape remain unclear. This review highlights the need for further investigation of mechanisms underlying tumor dormancy using clinically relevant models.

Keywords: Bone metastasis; Breast cancer; Tumor dormancy.

Fig. 1

Mechanisms regulating tumor dormancy in the bone. (a) Disseminated tumor cells (DTCs) home to the perivascular niche via bone microenvironmental factors such as CXCL12:CXCR4 and E-selectin. Within the perivascular niche, angiogenesis suppressors such as thrombospondin-1 (TSP1) promote tumor dormancy whereas proangiogenic factors including transforming growth factor beta 1 (TGFβ1) and periostin secreted from neovasculature induce tumor cell proliferation. DTCs prime mesenchymal stem cells to secrete exosomes containing miR-222/223 to maintain tumor cells in a dormant state. (b) DTCs residing in the endosteal niche co-opt the hematopoietic stem cell (HSC) niche to promote their survival and dormancy. Secretion of IL-1β and activation of mTOR signaling by CDH1:CDH2 interactions between osteoblasts and tumor cells stimulate tumor cell proliferation. (c) Tumor cell–intrinsic signaling pathways such as leukemia inhibitory factor receptor (LIFR), p38, and a hypoxia gene signature maintain tumor cells in a dormant state. CXCL12 = CXC chemokine ligand 12; CXCR4 = CXC motif chemokine receptor 4; CX3CL = CX3C motif chemokine ligand; CX3CR = CX3C motif chemokine receptor; TSP1 = thrombospondin-1; TGFβ1 = transforming growth factor beta 1; POSTN = periostin; HSC = hematopoietic stem cell; CDH1 = E-cadherin; CDH2 = N-cadherin; IL-1β = interleukin 1β; mTOR = mammalian target of rapamycin; LIFR = leukemia inhibitory factor receptor; STAT3 = signal transducer and activator of transcription 3; MSK1 = ribosomal protein S6 kinase A5; FBXW7 = F-box and WD repeat domain containing 7; IKKβ = inhibitor of nuclear factor kappa B kinase subunit beta; NR2F1 = nuclear receptor subfamily 2 group F member 1; p38 = mitogen activated protein kinase 14; ERK = extracellular-signal regulated kinase; BMP = bone morphogenetic protein; TGFβ2 = transforming growth factor beta 2