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

While tumoral Smad-mediated transforming growth factor beta (TGF beta) signaling drives osteolytic estrogen receptor alpha-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 TGF beta signaling in human ER+ cells and bone-tropic behavior following intracardiac inoculation of estrogen (E-2)-supplemented female nude mice. While all ER+ tumor cells tested (ZR-75-1, T47D, and MCF-7-derived) expressed TGF beta receptors II and I, only cells with TGF beta-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; TGF beta and E-2 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-TGF beta neutralizing antibody, significantly decreased osteolytic ER+ BMETs in association with a decrease in bone-resorbing osteoclasts at the tumor-bone interface. Thus, TGF beta may also be a driver of ER+ BMET osteolysis. Moreover, additive pro-osteolytic effects of tumoral E-2 and TGF beta signaling could at least partially explain the greater propensity for ER+ tumors to form BMETs, which are primarily osteolytic.

Automated summary

The study found that tumoral Smad-mediated TGF beta signaling plays a role in driving osteolytic bone metastases in estrogen receptor-positive (ER+) breast cancer. Additionally, the combination of TGF beta and estrogen induced PTHrP expression, leading to bone resorption, and treatment with a pan-TGF beta neutralizing antibody decreased osteolytic ER+ bone metastases.