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Page 2 of 18 Cheng et al. J Cancer Metastasis Treat 2021;7:17 https://dx.doi.org/10.20517/2394-4722.2021.27

cells.

Conclusion: These results suggest that tumoral ERα signaling may contribute to ER+ BMET-associated osteolysis,
potentially explaining the greater predilection for ER+ tumors to form clinically-evident osteolytic BMETs.

Keywords: Breast cancer, estrogen receptor, bone metastasis, estradiol, osteolysis, osteoclasts, parathyroid
hormone-related protein, bone

INTRODUCTION
Breast cancer is the most common female cancer in the world and the 2nd leading cause of cancer
mortality . The majority of women with metastatic breast cancer have bone metastases (BMETs), which are
[1]
[2,3]
primarily osteolytic . Eighty percent of women with breast cancer BMETs have ER+ tumors due to both
[4]
the higher incidence of this subtype and its 2-fold greater proclivity to form metastases in bone . This
association of BMETs in metastatic breast cancer with tumoral ERα expression, which remains highly
concordant between primary and bone metastatic tumors , introduces the possibility that tumor cell ERα
[5-7]
signaling within the bone milieu, independent of proliferative effects that are important but not site-specific,
may also be driving tumor-associated osteolysis, which is bone-specific, known to be dependent on tumor-
derived factors [8-11] , and of clear clinical relevance due to the morbidity and mortality associated with
osteolytic ER+ BMETs. However, a specific role for ERα signaling in driving tumor-induced osteolysis in
ER+ BMET has not, to our knowledge, been previously investigated. Given the frequent association of ERα-
positivity with BMETs, this question is highly relevant for the management of breast cancer, particularly
since many ER+ BMETs occur post-hormone therapy (HT) and/or are associated with ligand-independent
activating ER mutations [12,13] . If tumoral E signaling contributes to ER+ BMET progression by driving
2
tumor-associated osteolysis, targeting of specific downstream signaling pathways mediating this effect could
provide novel molecular approaches for skeletal therapeutics to block BMET progression for ER+ tumors.

Because mice, unlike humans, lack aromatase expression in mammary tissue and bone cells [14,15] and also
have 10-fold lower circulating 17β-estradiol (E ) levels than humans , the optimal growth of human ER+
[16]
2
breast cancer orthotopic tumors and osteolytic BMETs in preclinical murine models is dependent on
exogenous E supplementation [17,18,19-26,27,28] . This presents a challenge when studying murine models of
2
human ER+ BMETs given the responsiveness of both tumor and bone cells to E 2 [29-33] and the absence of
syngeneic models of murine ER+ breast cancer BMET. Indeed, the E doses required to promote ER+ breast
2
cancer growth in osteolytic xenograft models also increase murine bone mass [18,20,21,26,28,34] and furthermore,
can induce osteolytic murine osteosarcomas in some animals, as previously demonstrated by our
laboratory .
[34]
Evidence from ER-BMET models, which represent the majority of preclinical breast cancer BMET research,
has allowed for an assessment of the influence of estrogenic effects on the bone microenvironment,
independent of tumor cell ER signaling, on osteolytic ER- BMET progression. Taken together, these ER-
breast cancer xenograft studies suggest that both induction of bone formation by E -treatment [35,36] and bone
2
resorption by E -deprivation [via ovariectomy (OVX)] [28,37,38] promote ER- BMET progression. In ER+
2
BMET models, E bone-microenvironmental effects have often not been considered [19,21-26,39,40] and are rarely
2
documented [18,20,28] , while a role of tumor ERα signaling in driving tumor-associated osteolysis has not, to our
knowledge, previously been studied.

To address these knowledge gaps regarding the effects of ERα signaling in the tumor itself vs. the bone
microenvironment in driving tumor-associated osteolysis and osteolytic progression for ER+ BMET, E
2