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Author Spotlight: Exploring Salidroside's Molecular Mechanisms in Breast Cancer Treatment
Published on: June 9, 2023
A Novel Sulforaphane-Regulated Gene Network in Suppression of Breast Cancer-Induced Osteolytic Bone Resorption
Subrata K Pore1, Eun-Ryeong Hahm1, Su-Hyeong Kim1
1Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania.
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 dose-dependent manner upon addition of conditioned media from SFN-treated breast cancer cells representative of different subtypes. 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-κB 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.
Insights
Sulforaphane (SFN) suppresses breast cancer bone metastasis by inhibiting osteoclast differentiation. This orally bioavailable small molecule offers a potential new therapy for osteolytic bone resorption in breast cancer patients.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Bone metastasis is common in breast cancer, with current therapies like bisphosphonates and denosumab being palliative and having limitations.
- A significant unmet need exists for safe, orally bioavailable treatments to manage osteolytic bone resorption in breast cancer patients.
- Existing treatments for breast cancer bone metastases have limitations, including palliative effects and potential adverse events.
Purpose of the Study:
- To investigate the efficacy of sulforaphane (SFN), a clinically safe and orally bioavailable small molecule, in suppressing breast cancer-induced bone resorption.
- To elucidate the molecular mechanisms by which SFN affects osteoclast differentiation and bone resorption.
- To evaluate the in vitro and in vivo effects of SFN on osteolytic bone lesions.
Main Methods:
- In vitro assessment of osteoclast differentiation using conditioned media from SFN-treated breast cancer cells.
- Targeted microarrays and analysis of The Cancer Genome Atlas (TCGA) data to identify SFN-regulated gene signatures.
- In vivo studies using an intracardiac MDA-MB-231-Luc mouse model to assess SFN's effect on bone volume.
Main Results:
- SFN dose-dependently inhibited osteoclast differentiation in vitro.
- A novel SFN-regulated gene signature involving runt-related transcription factor 2 (RUNX2) and nuclear factor-κB (NF-κB) was identified.
- Oral SFN administration significantly suppressed osteolytic bone resorption in vivo, increasing bone volume in a preclinical model.
Conclusions:
- Sulforaphane (SFN) is a novel inhibitor of breast cancer-induced osteolytic bone resorption, demonstrating efficacy both in vitro and in vivo.
- SFN targets key regulators of osteoclastogenesis, including RUNX2 and NF-κB pathways.
- The findings support SFN as a promising therapeutic candidate for managing bone metastases in breast cancer.
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