Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer

Buijs, Jeroen T.; Henriquez, Nico V.; Overveld, Petra G.M. van; Horst, Geertje van der; Que, Ivo; Schwaninger, Ruth; Rentsch, Cyrill A.; Dijke, Peter ten; Cleton‐Jansen, Anne‐Marie; Driouch, Keltouma; Lidereau, Rosette; Bachelier, Richard; Vukičević, Slobodan; Clézardin, Philippe; Papapoulos, Socrates E.; Cecchini, Marco; Löwik, Clemens W.G.M.; Pluijm, Gabri van der

doi:10.1158/0008-5472.can-06-2490

Cited by 185 publications

(189 citation statements)

References 48 publications

(81 reference statements)

Supporting

Mentioning

178

Contrasting

Unclassified

Order By: Relevance

“…As expected (van der Pluijm et al, 2005;Buijs et al, 2007a), vehicle-treated cells readily formed multiple detectable bone metastases (Figures 5a-c).…”

Section: Heterodimeric and Homodimeric Bmp Molecules Differentially Asupporting

confidence: 77%

“…Even more, TGFb-induced EMT may render breast cancer cells with properties of stem cells and even therapy resistance (Mani et al, 2008;Creighton et al, 2009;Polyak and Weinberg, 2009;Singh and Settleman, 2010;van der Pluijm, 2010). Strikingly, BMP7 treatment can antagonize TGFb-induced EMT, and inhibit breast cancer growth and bone metastasis formation in vivo (Buijs et al, 2007a(Buijs et al, , 2007b. Nonetheless, the direct effects of BMPs on breast CSCs have not been addressed.…”

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

“…The human breast cancer cell line MDA-MB-231 (ATCC, Rockville, MD, USA) and the luciferase-expressing boneseeking clone MDA-MB-231-B/Luc þ were cultured in Dulbecco's modified Eagle's medium containing 4.5 g/l glucose and supplemented with 10% FCII (Hyclone, Etten-Leur, The Netherlands) as described previously (Buijs et al, 2007a). All cell lines were tested for Mycoplasma contamination by PCR prior to use.…”

Section: Cell Line and Culture Conditionsmentioning

confidence: 99%

“…The concept of CSCs underscores the importance of targeting the correct cells for cancer therapy, as eliminating only the rapidly dividing, more differentiated transit-amplifying cells by chemo-or radiotherapy is not likely to result in successful longterm remission if the less differentiated and slower proliferating CSCs remain to repopulate the tumor. Therefore, it has been postulated that the CSC population in solid cancers can be potentially affected by the so-called differentiation-inducing agents (Buijs et al, 2007a(Buijs et al, , 2007cvan der Pluijm, 2010).…”

Section: Introductionmentioning

confidence: 99%

“…Furthermore, an aggressive clone of the human MCF-7 breast cancer cell line showed, besides reduced BMP7 expression, upregulation of CD44 and downregulation of CD24 (Uchino et al, 2010), indicative of a CSC phenotype. We have demonstrated previously that BMP7 inhibited TGFb-induced EMT, stimulated the opposite process, a mesenchymal-to-epithelial transition, and inhibited bone metastasis formation in vivo (Buijs et al, 2007a(Buijs et al, , 2007b. To date, the effects of BMPs on breast CSCs have remained elusive.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

View full text Add to dashboard Cite

Accumulating evidence suggests that a subpopulation of breast cancer cells, referred to as cancer stem cells (CSCs), have the ability to propagate a tumor and potentially seed new metastases. Furthermore, stimulation of an epithelialto-mesenchymal transition by factors like transforming growth factor-b (TGFb) is accompanied with the generation of breast CSCs. Previous observations indicated that bone morphogenetic protein-7 (BMP7) antagonizes the protumorigenic and prometastatic actions of TGFb, but whether BMP7 action is mechanistically linked to breast CSCs has remained elusive. Here, we have studied the effects of BMP7, BMP2 and a BMP2/7 heterodimer on the formation of human breast CSCs (ALDH hi /CD44 hi / CD24 À/low ) and bone metastases formation in a preclinical model of intra-cardiac injection of MDA-MB-231 cells in athymic nude (Balb/c nu/nu) mice. The BMP2/7 heterodimer was the most efficient stimulator of BMP signaling and very effectively reduced TGFb-driven Smad signaling and cancer cell invasiveness. The tested BMPs-particularly the heterodimeric BMP2/7-strongly reduced the size of the ALDH hi /CD44 hi /CD24 À/low CSC subpopulation. In keeping with these in vitro observations, pretreatment of cancer cells with BMPs for 72 h prior to systemic inoculation of the cancer cells inhibited the formation of bone metastases. Collectively, our data support the notion that breast CSCs are involved in bone metastasis formation and describe heterodimeric BMP2/7 as a powerful TGFb antagonist with anti-metastatic potency.

show abstract

“…As expected (van der Pluijm et al, 2005;Buijs et al, 2007a), vehicle-treated cells readily formed multiple detectable bone metastases (Figures 5a-c).…”

Section: Heterodimeric and Homodimeric Bmp Molecules Differentially Asupporting

confidence: 77%

Section: Bmp2/7 Inhibits the Breast Cancer Stem Cell Subpopulation Jtmentioning

confidence: 99%

Section: Cell Line and Culture Conditionsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

et al. 2011

View full text Add to dashboard Cite

show abstract

Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer

Baek¹,

Pishvaian²,

Kim³

et al. 2011

Hepatology

View full text Add to dashboard Cite

Transforming growth factor beta (TGF-b) is an important regulator of cell growth, and loss of TGF-b signaling is a hallmark of carcinogenesis. The Smad3/4 adaptor protein b2-spectrin (b2SP) is emerging as a potent regulator of tumorigenesis through its ability to modulate the tumor suppressor function of TGF-b. However, to date the role of the TGFb signaling pathway at specific stages of the development of hepatocellular carcinoma (HCC), particularly in relation to the activation of other oncogenic pathways, remains poorly delineated. Here we identify a mechanism by which b2SP, a crucial Smad3 adaptor, modulates cyclin dependent kinase 4 (CDK4), cell cycle progression, and suppression of HCC. Increased expression of b2SP inhibits phosphorylation of the retinoblastoma gene product (Rb) and markedly reduces CDK4 expression to a far greater extent than other CDKs and cyclins. Furthermore, suppression of CDK4 by b2SP efficiently restores Rb hypophosphorylation and cell cycle arrest in G 1 . We further demonstrate that b2SP interacts with CDK4 and Smad3 in a competitive and TGF-b-dependent manner. In addition, haploinsufficiency of cdk4 in b2sp 1/2 mice results in a dramatic decline in HCC formation compared to that observed in b2sp 1/2 mice. Conclusion: b2SP deficiency leads to CDK4 activation and contributes to dysregulation of the cell cycle, cellular proliferation, oncogene overexpression, and the formation of HCCs. Our data highlight CDK4 as an attractive target for the pharmacologic inhibition of HCC and demonstrate the importance of b2sp 1/2 mice as a model of preclinical efficacy in the treatment of HCC. (HEPATOLOGY 2011;53:1676-1684 T he transforming growth factor b (TGF-b) signaling pathway is involved in multiple cellular processes, including cell growth, differentiation, adhesion, migration, and apoptosis. TGF-b is particularly active as an antimitogenic cytokine, functioning as a profound tumor suppressor by inhibiting cell cycle progression and arresting cells in early G 1 phase. TGFb signaling is mediated by type I and type II transmembrane serine/threonine kinase receptors (TbRI and TbRII) and such intracellular mediators as the Abbreviations: b2SP, b2-spectrin; CDK4, cyclin dependent kinase 4; HCC, hepatocellular cancer; TGF-b, transforming growth factor-b. From the

show abstract

Repulsive guidance molecule B (RGMB) plays negative roles in breast cancer by coordinating BMP signaling

Sanders

et al. 2012

J of Cellular Biochemistry

View full text Add to dashboard Cite

Repulsive guidance molecules (RGMs) coordinate axon formation and iron homestasis. These molecules are also known as co-receptors of bone morphogenetic proteins (BMPs). However, the role played by RGMs in breast cancer remains unclear. The present study investigated the impact of RGMB on functions of breast cancer cells and corresponding mechanisms. RGMB was knocked down in breast cancer cells by way of an anti-RGMB ribozyme transgene. Knockdown of RGMB resulted in enhanced capacities of proliferation, adhesion, and migration in breast cancer cells. Further investigations demonstrated RGMB knockdown resulted in a reduced expression and activity of Caspase-3, accompanied with better survival in RGMB knockdown cells under serum starvation, which might be induced by its repression on MAPK JNK pathway. Up-regulations of Snai1, Twist, FAK, and Paxillin via enhanced Smad dependent sigaling led to increased capacities of adhesion and migration. Our current data firstly revealed that RGMB may act as a negative regulator in breast cancer through BMP signaling.

show abstract

Bone Morphogenetic Protein 7 in the Development and Treatment of Bone Metastases from Breast Cancer

Cited by 185 publications

References 48 publications

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

The BMP2/7 heterodimer inhibits the human breast cancer stem cell subpopulation and bone metastases formation

Transforming growth factor-β adaptor, β2-spectrin, modulates cyclin dependent kinase 4 to reduce development of hepatocellular cancer

Repulsive guidance molecule B (RGMB) plays negative roles in breast cancer by coordinating BMP signaling

Contact Info

Product

Resources

About