A Role for TGFβ Signaling in Preclinical Osteolytic Estrogen Receptor-Positive Breast Cancer Bone Metastases Progression

Abstract

While 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.

The Roadmap of RANKL/RANK Pathway in Cancer

“…However, analysis of clinical series looking at disseminated tumors cells in bone marrow suggests that the longer a woman is post-menopausal, the less attractive bone microenvironment is for tumor cells [62,63]. A recent study has shown that estradiol and TGF-β upregulate PTHrP in ER+ osteotropic BCa cells [64] and increase the progression of osteolytic metastases in ER-negative BCa cells [65]. Therefore, estrogen deficiency may contribute to the benefit of adjuvant BPs in bone recurrence in post-menopausal women, while in metastatic settings, the menopausal status does not affect outcomes related to BTAs [66].…”

Nanoparticles for the Treatment of Bone Metastasis in Breast Cancer: Recent Advances and Challenges

“… 157 In an estradiol-dependent ER+ BCBM mouse model, Erα increased the production of the tumor osteolytic factor parathyroid hormone-related protein, the number of osteoclasts at the bone–tumor interface, and osteolytic bone damage in an estradiol-dependent manner, which explains the propensity of ER+ tumors to develop osteolytic pathologies. 158 Considering the risk of bone metastasis in ER-overexpressing BC, augmenting ER-targeted therapy may provide new treatment avenues for this BC subtype and improve survival.…”

Biological and Clinical Aspects of Metastatic Spinal Tumors

“…TGF-β is produced by active osteoclasts and increases the production of PTHrP. The research on samples of MDA-MB-231 breast cancer cells with neutralized TGF-β shows a significant decrease in osteolytic lesions [ 112 ].…”