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Page 2 of 20 Ottewell et al. J Cancer Metastasis Treat 2021;7:11 https://dx.doi.org/10.20517/2394-4722.2021.14

INTRODUCTION
Bone is a common metastatic site for breast cancer and is most prevalent from oestrogen receptor (ER)-
[1]
positive disease . Once in bone, cancers are currently considered to be incurable and life expectancy for
patients’ drops to just 2-4 years following diagnosis of bone involvement . It is therefore imperative that
[2]
researchers better understand the mechanisms that drive the different stages of the bone metastatic process
to enable development of more effective and curative therapies.

Metastasis is a complex, multistep process involving genetic and phenotypic changes in tumour cells and
cells within the local environment. In addition, evidence suggests that signalling between tumour cells and
bone cells is an early event, in which tumour cells at the primary site produce microRNAs and other
secreted factors, such as Lysyl oxidase and interleukin 1 beta, that prime bone for receiving metastatic cells
and in return bone cells secrete chemo attractants that promote tumour cell homing to this site . The
[3-6]
complex nature of this process necessitates the use of whole-body organisms. However, unlike humans,
spontaneous metastasis of primary mammary tumours to bone is rare in mice and no syngeneic models of
ER-positive disease have been reported. To date, there is no single model that authentically reproduces all of
the genetic and phenotypic changes representative of human bone metastasis, therefore researchers must
select the most appropriate model(s) to test their hypotheses. In this review, we discuss the traditional and
novel mouse models that are used to study bone metastasis from breast cancer, focusing on advances that
have been made towards making these models more closely related to human disease in an attempt to
improve translational efficacy between the laboratory and the clinic.

BREAST CANCER BONE METASTASIS; WHAT ARE WE TRYING TO MODEL?
Seventy to eight per cent of patients with late-stage breast cancer will develop bone metastasis and the
majority of these patients will have ER-positive disease . Dissemination of tumour cells into bone is
[1]
believed to be an early event, often occurring before clinical detection of the primary tumour. However,
overt metastases do not usually develop until many years later . When tumour cells arrive in the bone
[1]
microenvironment, they home to the bone metastatic niche (comprised of the endosteal/haematopoietic
[7,8]
stem cell and peri-vascular niches) . Interactions between tumour cells and the niche(s) promote tumour
cell dormancy and/or metastatic outgrowth, dependent upon a number of factors including tumour volume,
stage, molecular sub-type and environmental conditions. Typically, ER-negative tumours display a more
aggressive phenotype with disease recurrence peaking around two years after diagnosis and relapse rate
reducing to low levels > 5 years after diagnosis. Whereas less aggressive ER-positive breast cancer has a long
latency, with low risk of recurrence in the initial five years after diagnosis, the risk of recurrence increasing
[9]
annually after five years following both diagnosis and surgical removal of the primary tumour .
Interestingly, the 15-year recurrence is similar in both ER-negative and ER-positive disease, suggesting that
both molecular subtypes contain a population of cells capable of undergoing long-term dormancy in
bone . It is believed that long periods of latency associated with bone metastasis are due to disseminated
[10]
tumour cells either needing time to alter their new environment to enable increased metastatic outgrowth of
tumour cells through expansion of the metastatic niche(s)/suppression of immune regulation or waiting
until external factors alter the local microenvironment in a manner that promotes tumour growth. Once
tumour cells begin to outgrow into overt metastasis in bone, they stimulate increased resorption of the bone
matrix, through receptor activator of nuclear factor κ B (RANK)/RANK ligand (RANKL)-induced
activation of osteoclasts, resulting in the formation of osteolytic lesions in the affected bone and release of
matrix-bound cytokines, including interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFα), which
feedback onto the tumour cells further stimulating their growth. These interactions between tumour cells
and bone cells cause a positive feedback loop known as the vicious cycle of bone metastasis
(reviewed in [11,12] ). It must be noted, however, that bone metastases from breast cancers are not exclusively