TY - JOUR
T1 - Differential regulation of breast cancer bone metastasis by PARP1 and PARP2
AU - Zuo, Hao
AU - Yang, Dengbao
AU - Yang, Qiwen
AU - Tang, Haidong
AU - Fu, Yang Xin
AU - Wan, Yihong
N1 - Funding Information:
We thank University of Texas Southwestern histology pathology core, flow cytometry core, and next-generation sequencing core for their assistance in our studies; F. Dantzer and W. L. Kraus for the PARP1 and PARP2 KO, and flox mice; W. L. Kraus for the plasmids for human and mouse PARP1 and PARP2, and shPARP1 and shPARP2; S. Morrison, P. Dechow, J. Feng, and C. Qin for assistance with μCT, histomorphometry, and X-ray analysis. We also thank University of Texas Southwestern Small-Animal Imaging Resource, which is supported in part by the Harold C. Simmons Cancer Center through an NCI Cancer Center Support Grant, 1P30 CA142543-01 and The Department of Radiology. Y.W. is Lawrence Raisz Professor in Bone Cell Metabolism and a Virginia Murchison Linthicum Scholar in Medical Research. This work was in part supported by NIH/NCI (R01CA229487, R01CA236802, Y.W.), CPRIT (RP180047, Y.W.), and DOD (W81XWH-18-1-0014, Y.W.), The Welch Foundation (I-1751, Y.W.) and UTSW Endowed Scholar Startup Fund (Y.W.). The VisualSonics Vevo 770 was purchased with National Institutes of Health American Recovery and Reinvestment Act stimulus funds 1S10RR02564801.
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - 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.
AB - 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.
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U2 - 10.1038/s41467-020-15429-z
DO - 10.1038/s41467-020-15429-z
M3 - Article
C2 - 32221289
AN - SCOPUS:85082535504
VL - 11
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1578
ER -