A role for tgfβ signaling in preclinical osteolytic estrogen receptor-positive breast cancer bone metastases progression
AffiliationCancer Biology Graduate Interdisciplinary Program, University of Arizona
Department of Medicine, University of Arizona
Department of Nutritional Sciences, University of Arizona
Department of Cellular and Molecular Medicine, University of Arizona
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CitationCheng, J. N., Frye, J. B., Whitman, S. A., Kunihiro, A. G., Pandey, R., & Funk, J. L. (2021). A role for tgfβ signaling in preclinical osteolytic estrogen receptor-positive breast cancer bone metastases progression. International Journal of Molecular Sciences, 22(9).
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AbstractWhile tumoral Smad-mediated transforming growth factor β (TGFβ) signaling drives osteolytic estrogen receptor α-negative (ER-) breast cancer bone metastases (BMETs) in preclinical models, its role in ER+ BMETs, representing the majority of clinical BMETs, has not been documented. Experiments were undertaken to examine Smad-mediated TGFβ signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E2 )-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGFβ receptors II and I, only cells with TGFβ-inducible Smad signaling (MCF-7) formed osteolytic BMETs in vivo. Regulated secretion of PTHrP, an osteolytic factor expressed in >90% of clinical BMETs, also tracked with osteolytic potential; TGFβ and E2 each induced PTHrP in bone-tropic or BMET-derived MCF-7 cells, with the combination yielding additive effects, while in cells not forming BMETs, PTHrP was not induced. In vivo treatment with 1D11, a pan-TGFβ neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGFβ may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E2 and TGFβ signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.
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Except where otherwise noted, this item's license is described as Copyright © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).