Select HDAC Inhibitors Enhance Osteolysis and Bone Metastasis Outgrowth but Can Be Mitigated With Bisphosphonate Therapy.

Breast cancer has a high predilection for spreading to bone with approximately 70% of patients who succumb to disease harboring bone disseminated tumor cells. Despite this high prevalence, treatments for bone metastatic breast cancer predominantly manage morbidities, including pain and hypercalcemia, rather than reducing bone metastasis incidence or growth. Histone deacetylase inhibitors (HDACi), including panobinostat, entinostat, and valproic acid, typically slow primary tumor progression and are currently in clinical trials for the treatment of many cancers, including primary and metastatic breast cancer, but their effects on bone metastatic disease have not been examined in preclinical models. We report that treatment with the HDACi panobinostat, but not entinostat or valproic acid, significantly reduced trabecular bone volume in tumor-naïve mice, consistent with previous reports of HDACi-induced bone loss. Surprisingly, treatment with entinostat or panobinostat, but not valproic acid, increased tumor burden and incidence in an experimental model of breast cancer bone metastasis. In vitro, multiple HDACi stimulated expression of pro-osteolytic genes in breast tumor cells, suggesting this may be a mechanism by which HDACi fuel tumor growth. In support of this, combination therapy of panobinostat or entinostat with the antiresorptive bisphosphonate zoledronic acid prevented bone metastatic progression; however, the addition of zoledronic acid to panobinostat therapy failed to fully correct panobinostat-induced bone loss. Together these data demonstrate that select HDACi fuel bone metastatic growth and provide potential mechanistic and therapeutic avenues to offset these effects. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

HDAC inhibitors induce LIFR expression and promote a dormancy phenotype in breast cancer.

Despite advances in breast cancer treatment, residual disease driven by dormant tumor cells continues to be a significant clinical problem. Leukemia inhibitory factor receptor (LIFR) promotes a dormancy phenotype in breast cancer cells and LIFR loss is correlated with poor patient survival. Herein, we demonstrate that histone deacetylase inhibitors (HDACi), which are in phase III clinical trials for breast cancer, epigenetically induced LIFR and activated a pro-dormancy program in breast cancer cells. HDACi slowed breast cancer cell proliferation and reduced primary tumor growth. Primary breast tumors from HDACi-treated patients had increased LIFR levels and reduced proliferation rates compared to pre-treatment levels. Recent Phase II clinical trial data studying entinostat and azacitidine in metastatic breast cancer revealed that induction of several pro-dormancy genes post-treatment was associated with prolonged patient survival. Together, these findings suggest HDACi as a potential therapeutic avenue to promote dormancy, prevent recurrence, and improve patient outcomes in breast cancer.