A Novel Sulforaphane-Regulated Gene Network in Suppression of Breast Cancer–Induced Osteolytic Bone Resorption

Abstract

Bone is the most preferred site for colonization of metastatic breast cancer cells for each subtype of the disease. The standard of therapeutic care for breast cancer patients with bone metastasis includes bisphosphonates (e.g., zoledronic acid), which have poor oral bioavailability, and a humanized antibody (denosumab). However, these therapies are palliative, and a subset of patients still develop new bone lesions and/or experience serious adverse effects. Therefore, a safe and orally bioavailable intervention for therapy of osteolytic bone resorption is still a clinically unmet need. This study demonstrates suppression of breast cancer-induced bone resorption by a small molecule (sulforaphane, SFN) that is safe clinically and orally bioavailable. In vitro osteoclast differentiation was inhibited in a dosedependent manner upon addition of conditioned media from SFN-treated breast cancer cells representative of different sub-types. Targeted microarrays coupled with interrogation of The Cancer Genome Atlas data set revealed a novel SFN-regulated gene signature involving cross-regulation of runt-related transcription factor 2 (RUNX2) and nuclear factor-kB and their downstream effectors. Both RUNX2 and p65/p50 expression were higher in human breast cancer tissues compared with normal mammary tissues. RUNX2 was recruited at the promotor of NFKB1. Inhibition of osteoclast differentiation by SFN was augmented by doxycycline-inducible stable knockdown of RUNX2. Oral SFN administration significantly increased the percentage of bone volume/total volume of affected bones in the intracardiac MDA-MB-231-Luc model indicating in vivo suppression of osteolytic bone resorption by SFN. These results indicate that SFN is a novel inhibitor of breast cancer-induced osteolytic bone resorption in vitro and in vivo.

Preclinical Efficacy and Involvement of AKT, mTOR, and ERK Kinases in the Mechanism of Sulforaphane against Endometrial Cancer

“…This growth inhibition involved G 2 /M cell cycle arrest, consistent with reported observations in acute lymphoblastic leukemia, ovarian cancer and colon cancer [15,47,48]. G 2 /M cell cycle arrest is a checkpoint induced by DNA damage that is controlled by a p21/cdc2/cyclin B1 [15,21,28]. In endometrial cancer cell lines, sulforaphane induced phosphorylation of cdc2 on Tyr15, which is consistent with inhibition of the p21/cdc2/cyclin B1 complex driving G2/M progression.…”

“…The chemopreventive and therapeutic effects of sulforaphane have been comprehensively investigated in various cancers in vitro and in vivo [17]; however, it has not yet been studied in endometrial cancers. The safety of sulforaphane and sulforaphane-rich broccoli sprout extract (sulforaphane-BSE) has been tested clinically [20,21], and multiple phase I and phase II trials have been completed evaluating the efficacy of sulforaphane amongst patients with prostate cancer and breast cancer. These promising activities suggest that sulforaphane may also have value for use in endometrial cancer treatment regimens.…”

OSU-03012 Disrupts Akt Signaling and Prevents Endometrial Carcinoma Progression in vitro and in vivo

“…The cell cycle arrest at the G2/M phase is a DNA damage checkpoint controlled by p21/cdc2/cyclin B1. 34 In EC cell lines, OSU-03012 induced P21 upregulation, which is consistent with the inhibition of the p21/cdc2/cyclin B1 complex responsible for G2 to M cell cycle regulation.…”

Sulforaphane Inhibits Osteoclastogenesis via Suppression of the Autophagic Pathway

“…As a pleiotropic compound, SFN is known to protect cells from deoxyribonucleic acid (DNA) damage and to modulate cell proliferation, apoptosis, angiogenesis, invasion, and metastasis in cancer [ 21 , 22 , 23 , 24 ]. Recently, it was reported that SFN could also be used to treat diseases associated with pathological bone resorption, such as bone metastasis in breast cancer, osteoporosis, and osteoarthritis [ 25 , 26 , 27 ]. In addition, Tomohiro Takagi et al suggested that SFN plays a negative role in RANKL-induced osteoclastogenesis, but the underlying mechanisms need to be further investigated [ 10 , 28 ].…”