Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-β signaling at the tumor-bone interface

Kalyan C. Nannuru, Mitsuru Futakuchi, Michelle L. Varney, Thomas M. Vincent, Eric G. Marcusson, Rakesh K Singh

Research output: Contribution to journalArticle

76 Citations (Scopus)

Abstract

The tropism of breast cancer cells for bone and their tendency to induce an osteolytic phenotype are a result of interactions between breast cancer cells and stromal cells and are of paramount importance for bone metastasis. However, the underlying molecular mechanisms remain poorly understood. We hypothesize that tumor-stromal interaction alters gene expression in malignant tumor cells and stromal cells creating a unique expression signature that promotes osteolytic breast cancer bone metastasis and that inhibition of such interactions can be developed as targeted therapeutics. Microarray analysis was performed to investigate gene expression profiling at the tumor-bone (TB) interface versus the tumor alone area from syngenic mice injected with three different syngenic mammary tumor cell lines that differ in their metastatic potential. We identified matrix metalloproteinase 13 (MMP13), receptor activator of NF-κB ligand (RANKL), and integrins binding sialoprotein to be genes upregulated at the TB interface and validated. To determine the functional role of MMP13 in tumor-induced osteolysis, mice with Cl66 mammary tumors were treated with MMP13 antisense oligonucleotides (MMP13-ASO) or control scrambled oligonucleotides (control-ASO). Knockdown of MMP13 expression at the TB interface leads to significant reduction in bone destruction and in the number of activated osteoclasts at the TB interface. Further analysis to evaluate the mechanism of MMP13-dependent osteolytic bone metastasis revealed that MMP13-ASO treatment decreased active MMP9, RANKL levels, and transforming growth factor-β signaling at the TB interface. Together, our data indicate that upregulation of MMP13 at the TB interface is important in tumor-induced osteolysis and suggest that MMP13 is a potential therapeutic target for breast cancer bone metastasis.

Original languageEnglish (US)
Pages (from-to)3494-3504
Number of pages11
JournalCancer Research
Volume70
Issue number9
DOIs
StatePublished - May 1 2010

Fingerprint

Matrix Metalloproteinase 13
Osteolysis
Transforming Growth Factors
Breast Neoplasms
Bone and Bones
Neoplasms
Bone Neoplasms
Neoplasm Metastasis
Stromal Cells
Integrin-Binding Sialoprotein
Tropism
Antisense Oligonucleotides
Gene Expression Profiling
Osteoclasts
Microarray Analysis
Tumor Cell Line
Oligonucleotides
Up-Regulation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-β signaling at the tumor-bone interface. / Nannuru, Kalyan C.; Futakuchi, Mitsuru; Varney, Michelle L.; Vincent, Thomas M.; Marcusson, Eric G.; Singh, Rakesh K.

In: Cancer Research, Vol. 70, No. 9, 01.05.2010, p. 3494-3504.

Research output: Contribution to journalArticle

Nannuru, Kalyan C. ; Futakuchi, Mitsuru ; Varney, Michelle L. ; Vincent, Thomas M. ; Marcusson, Eric G. ; Singh, Rakesh K. / Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-β signaling at the tumor-bone interface. In: Cancer Research. 2010 ; Vol. 70, No. 9. pp. 3494-3504.
@article{df55456891dd4f1aa7505e30768ca7a5,
title = "Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-β signaling at the tumor-bone interface",
abstract = "The tropism of breast cancer cells for bone and their tendency to induce an osteolytic phenotype are a result of interactions between breast cancer cells and stromal cells and are of paramount importance for bone metastasis. However, the underlying molecular mechanisms remain poorly understood. We hypothesize that tumor-stromal interaction alters gene expression in malignant tumor cells and stromal cells creating a unique expression signature that promotes osteolytic breast cancer bone metastasis and that inhibition of such interactions can be developed as targeted therapeutics. Microarray analysis was performed to investigate gene expression profiling at the tumor-bone (TB) interface versus the tumor alone area from syngenic mice injected with three different syngenic mammary tumor cell lines that differ in their metastatic potential. We identified matrix metalloproteinase 13 (MMP13), receptor activator of NF-κB ligand (RANKL), and integrins binding sialoprotein to be genes upregulated at the TB interface and validated. To determine the functional role of MMP13 in tumor-induced osteolysis, mice with Cl66 mammary tumors were treated with MMP13 antisense oligonucleotides (MMP13-ASO) or control scrambled oligonucleotides (control-ASO). Knockdown of MMP13 expression at the TB interface leads to significant reduction in bone destruction and in the number of activated osteoclasts at the TB interface. Further analysis to evaluate the mechanism of MMP13-dependent osteolytic bone metastasis revealed that MMP13-ASO treatment decreased active MMP9, RANKL levels, and transforming growth factor-β signaling at the TB interface. Together, our data indicate that upregulation of MMP13 at the TB interface is important in tumor-induced osteolysis and suggest that MMP13 is a potential therapeutic target for breast cancer bone metastasis.",
author = "Nannuru, {Kalyan C.} and Mitsuru Futakuchi and Varney, {Michelle L.} and Vincent, {Thomas M.} and Marcusson, {Eric G.} and Singh, {Rakesh K}",
year = "2010",
month = "5",
day = "1",
doi = "10.1158/0008-5472.CAN-09-3251",
language = "English (US)",
volume = "70",
pages = "3494--3504",
journal = "Cancer Research",
issn = "0008-5472",
publisher = "American Association for Cancer Research Inc.",
number = "9",

}

TY - JOUR

T1 - Matrix metalloproteinase (MMP)-13 regulates mammary tumor-induced osteolysis by activating MMP9 and transforming growth factor-β signaling at the tumor-bone interface

AU - Nannuru, Kalyan C.

AU - Futakuchi, Mitsuru

AU - Varney, Michelle L.

AU - Vincent, Thomas M.

AU - Marcusson, Eric G.

AU - Singh, Rakesh K

PY - 2010/5/1

Y1 - 2010/5/1

N2 - The tropism of breast cancer cells for bone and their tendency to induce an osteolytic phenotype are a result of interactions between breast cancer cells and stromal cells and are of paramount importance for bone metastasis. However, the underlying molecular mechanisms remain poorly understood. We hypothesize that tumor-stromal interaction alters gene expression in malignant tumor cells and stromal cells creating a unique expression signature that promotes osteolytic breast cancer bone metastasis and that inhibition of such interactions can be developed as targeted therapeutics. Microarray analysis was performed to investigate gene expression profiling at the tumor-bone (TB) interface versus the tumor alone area from syngenic mice injected with three different syngenic mammary tumor cell lines that differ in their metastatic potential. We identified matrix metalloproteinase 13 (MMP13), receptor activator of NF-κB ligand (RANKL), and integrins binding sialoprotein to be genes upregulated at the TB interface and validated. To determine the functional role of MMP13 in tumor-induced osteolysis, mice with Cl66 mammary tumors were treated with MMP13 antisense oligonucleotides (MMP13-ASO) or control scrambled oligonucleotides (control-ASO). Knockdown of MMP13 expression at the TB interface leads to significant reduction in bone destruction and in the number of activated osteoclasts at the TB interface. Further analysis to evaluate the mechanism of MMP13-dependent osteolytic bone metastasis revealed that MMP13-ASO treatment decreased active MMP9, RANKL levels, and transforming growth factor-β signaling at the TB interface. Together, our data indicate that upregulation of MMP13 at the TB interface is important in tumor-induced osteolysis and suggest that MMP13 is a potential therapeutic target for breast cancer bone metastasis.

AB - The tropism of breast cancer cells for bone and their tendency to induce an osteolytic phenotype are a result of interactions between breast cancer cells and stromal cells and are of paramount importance for bone metastasis. However, the underlying molecular mechanisms remain poorly understood. We hypothesize that tumor-stromal interaction alters gene expression in malignant tumor cells and stromal cells creating a unique expression signature that promotes osteolytic breast cancer bone metastasis and that inhibition of such interactions can be developed as targeted therapeutics. Microarray analysis was performed to investigate gene expression profiling at the tumor-bone (TB) interface versus the tumor alone area from syngenic mice injected with three different syngenic mammary tumor cell lines that differ in their metastatic potential. We identified matrix metalloproteinase 13 (MMP13), receptor activator of NF-κB ligand (RANKL), and integrins binding sialoprotein to be genes upregulated at the TB interface and validated. To determine the functional role of MMP13 in tumor-induced osteolysis, mice with Cl66 mammary tumors were treated with MMP13 antisense oligonucleotides (MMP13-ASO) or control scrambled oligonucleotides (control-ASO). Knockdown of MMP13 expression at the TB interface leads to significant reduction in bone destruction and in the number of activated osteoclasts at the TB interface. Further analysis to evaluate the mechanism of MMP13-dependent osteolytic bone metastasis revealed that MMP13-ASO treatment decreased active MMP9, RANKL levels, and transforming growth factor-β signaling at the TB interface. Together, our data indicate that upregulation of MMP13 at the TB interface is important in tumor-induced osteolysis and suggest that MMP13 is a potential therapeutic target for breast cancer bone metastasis.

UR - http://www.scopus.com/inward/record.url?scp=77951709842&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=77951709842&partnerID=8YFLogxK

U2 - 10.1158/0008-5472.CAN-09-3251

DO - 10.1158/0008-5472.CAN-09-3251

M3 - Article

VL - 70

SP - 3494

EP - 3504

JO - Cancer Research

JF - Cancer Research

SN - 0008-5472

IS - 9

ER -