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Differential regulation of breast cancer bone metastasis by PARP1 and PARP2
Hao Zuo1, Dengbao Yang1, Qiwen Yang1
1Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
Abstract:
PARP1 and PARP2 dual inhibitors, such as olaparib, have been recently FDA approved for the treatment of advanced breast and ovarian cancers. However, their effects on bone mass and bone metastasis are unknown. Here we show that olaparib increases breast cancer bone metastasis through PARP2, but not PARP1, specifically in the myeloid lineage, but not in the cancer cells. Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss. Intriguingly, myeloid deletion of PARP2, but not PARP1, increases the population of immature myeloid cells in bone marrow, and impairs the expression of chemokines such as CCL3 through enhancing the transcriptional repression by β-catenin. Compromised CCL3 production in turn creates an immune-suppressive milieu by altering T cell subpopulations. Our findings warrant careful examination of current PARP inhibitors on bone metastasis and bone loss, and suggest cotreatment with CCL3, β-catenin inhibitors, anti-RANKL or bisphosphonates as potential combination therapy for PARP inhibitors.
Insights
Olaparib, a PARP inhibitor, unexpectedly worsens breast cancer bone metastasis and bone loss by affecting myeloid cells. This suggests potential combination therapies to mitigate these side effects.
Area of Science:
- Oncology
- Immunology
- Bone Biology
Background:
- Poly (ADP-ribose) polymerase (PARP) inhibitors like olaparib are FDA-approved for advanced breast and ovarian cancers.
- The impact of PARP inhibitors on bone metastasis and bone mass remains largely unknown.
Purpose of the Study:
- To investigate the effects of olaparib on breast cancer bone metastasis and bone mass.
- To elucidate the specific roles of PARP1 and PARP2 in myeloid cells and cancer cells regarding bone metastasis.
Main Methods:
- Utilized olaparib treatment and genetic deletion of PARP1/2 in mouse models.
- Analyzed osteoclast differentiation, bone mass, myeloid cell populations, chemokine expression (CCL3), and T cell subpopulations.
Main Results:
- Olaparib treatment or PARP1/2 deletion promotes osteoclast differentiation and bone loss.
- Myeloid-specific PARP2 deletion, not PARP1, increases immature myeloid cells and impairs CCL3 expression via β-catenin.
- Reduced CCL3 leads to an immune-suppressive environment and altered T cell populations.
Conclusions:
- Olaparib exacerbates breast cancer bone metastasis and bone loss, mediated by PARP2 in myeloid cells.
- Findings highlight the need to evaluate PARP inhibitors' effects on bone health.
- Potential combination therapies include CCL3, β-catenin inhibitors, anti-RANKL, or bisphosphonates.
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