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Cheng et al. J Cancer Metastasis Treat 2021;7:17 Journal of Cancer
DOI: 10.20517/2394-4722.2021.27
Metastasis and Treatment

Original Article Open Access

Osteolytic effects of tumoral estrogen signaling in
an estrogen receptor-positive breast cancer bone

metastasis model

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Julia N. Cheng , Jennifer B. Frye , Susan A. Whitman , Andrew G. Kunihiro , Julia A. Brickey , Janet L.
Funk 2,3
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Cancer Biology Graduate Interdisciplinary Program, University of Arizona, Tucson, AZ 85724, USA.
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Department of Medicine, University of Arizona, Tucson, AZ 85724, USA.
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Department of Nutritional Sciences, University of Arizona, Tucson, AZ 85724, USA.
Correspondence to: Prof. Janet L. Funk, Department of Medicine, University of Arizona, P.O. Box 24-5218, Tucson, AZ 85724,
USA. E-mail: jfunk@email.arizona.edu
How to cite this article: Cheng JN, Frye JB, Whitman SA, Kunihiro AG, Brickey JA, Funk JL. Osteolytic effects of tumoral estrogen
signaling in an estrogen receptor-positive breast cancer bone metastasis model. J Cancer Metastasis Treat 2021;7:17.
https://dx.doi.org/10.20517/2394-4722.2021.27
Received: 30 Jan 2021 First Decision: 1 Mar 2021 Revised: 11 Mar 2021 Accepted: 18 Mar 2021 Available online: 8 Apr 2021

Academic Editors: Robert Coleman, Lucio Miele Copy Editor: Xi-Jun Chen Production Editor: Xi-Jun Chen

Abstract
Aim: Estrogen receptor α-positive (ER+) subtypes of breast cancer have the greatest predilection for forming
osteolytic bone metastases (BMETs). Because tumor-derived factors mediate osteolysis, a possible role for
tumoral ERα signaling in driving ER+ BMET osteolysis was queried using an estrogen (E )-dependent ER+ breast
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cancer BMET model.

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Methods: Female athymic Foxn1 mice were inoculated with human ER+ MCF-7 breast cancer cells via the left
cardiac ventricle post-E pellet placement, and age- and dose-dependent E effects on osteolytic ER+ BMET
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progression, as well as direct bone effects of E , were determined.
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Results: Osteolytic BMETs, which did not form in the absence of E supplementation, occurred with the same
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frequency in young (5-week-old) vs. skeletally mature (16-week-old) E (0.72 mg)-treated mice, but were larger in
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young mice where anabolic bone effects of E were greater. However, in mice of a single age and across a range of
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E doses, anabolic E bone effects were constant, while osteolytic ER+ BMET lesion incidence and size increased in
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an E dose-dependent fashion. Osteoclasts in ER+ tumor-bearing (but not tumor-naive) mice increased in an E -
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dose dependent fashion at the bone-tumor interface, while histologic tumor size and proliferation did not vary with
E dose. E -inducible tumoral secretion of the osteolytic factor parathyroid hormone-related protein (PTHrP) was
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dose-dependent and mediated by ERα, with significantly greater levels of secretion from ER+ BMET-derived tumor
© The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, sharing,
adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as
long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and
indicate if changes were made.
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