Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Takahashi, Mina; Otsuka, Fumio; Miyoshi, Tomoko; Otani, Hiroyuki; Goto, Junko; Yamashita, Misuzu; Ogura, Toshio; Makino, Hírofumi; Doihara, Hiroyoshi

doi:10.1677/joe-08-0226

Cited by 68 publications

(66 citation statements)

References 61 publications

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“…BMP6 neutralization in sera exerted little influence on cell growth (Fig. 9A), implying that BMP6 was not directly involved in regulating cancer cell growth, in agreement with the previous results [49,50]. DFO (at 100 μM) was used as a control to repress cell proliferation (Fig.…”

Section: Iron and Il-6 Jointly Promoted Tumor Cell Growthsupporting

confidence: 90%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

109

139

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Iron homeostasis is strictly governed in mammals; however, disordered iron metabolism (such as excess iron burden) is recognized as a risk factor for various types of diseases including cancers. Burgeoning evidence indicates that the central signaling of iron homeostasis, the hepcidin-ferroportin axis, is misregulated in cancers. Nonetheless, the mechanisms of misregulated expression of iron-related genes along this signaling in cancers remain largely unknown. In the current study, we found increased levels of serum hepcidin in breast cancer patients. Reduction of hepatic hepcidin through administration of heparin restrained tumorigenic properties of breast tumor cells. Mechanistic investigation revealed that increased iron, bone morphogenetic protein-6 (BMP6) and interleukin-6 (IL-6) jointly promoted the synthesis of hepatic hepcidin. Tumor hepcidin expression was marginally increased in breast tumors relative to adjacent tissues. In contrast, tumor ferroportin concentration was greatly reduced in breast tumors, especially in malignant tumors, compared to adjacent tissues. Elevation of ferroportin concentration inhibited cell proliferation in vitro and in vivo by knocking down tumor hepcidin expression. Additionally, increased IL-6 was demonstrated to jointly enhance the tumorigenic effects of iron through enforcing cell growth. Our combined data overall deciphered the machinery that altered the hepcidin-ferroportin signaling in breast cancers. Thus, targeting the hepcidin-ferroportin signaling would represent a promising therapeutics to restrain breast cancer growth.

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Section: Iron and Il-6 Jointly Promoted Tumor Cell Growthsupporting

confidence: 90%

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Zhang

Chen

Guo

et al. 2014

Cellular Signalling

109

139

View full text Add to dashboard Cite

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“…The results showed that inhibition of the expression of BMP6 significantly enhanced cell proliferation. Notably, BMP6 was found to inhibit cell proliferation in various cancer types including breast cancer, multiple myeloma, prostate cancer and skin tumors via multiple mechanisms including suppression of the p38-MAPK signaling pathway, cell cycle arrest and downregulation of AP-1 expression (17)(18)(19)(20). These data suggest that BMP6 may be a new diagnostic marker of breast cancer, and deregulation of BMP6 is involved in loss of proliferation control and failure to undergo cellular differentiation during tumorigenesis.…”

Section: Discussionmentioning

confidence: 95%

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Lian

Liu

et al. 2013

Oncology Reports

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Abstract. Previous studies indicate that bone morphogenetic protein (BMP) 6 is involved in breast cancer development and progression. However, the mechanism underlying the role of BMP6 in breast cancer cell proliferation, differentiation and chemoresistance remains unknown. In this study, we confirmed that BMP6 expression was downregulated in breast cancer tissues compared with the adjacent normal breast tissues. We further demonstrated that the downregulation of BMP6 was correlated with the estrogen receptor (ER) and progesterone receptor (PR) status, tumor grade and enhanced proliferation (Ki67 proliferation index). In vitro functional experiments showed that the suppression of BMP6 expression by a specific small hairpin (sh)RNA vector led to increased proliferation in the MCF7 breast cancer cell line. Furthermore, knockdown of BMP6 in MCF7 cells enhanced the chemoresistance to doxorubicin by upregulation of mdr-1/P-gp expression and activation of the ERK signaling pathway. Taken together, our data suggest that BMP6 plays a critical role in breast cancer cell aberrant proliferation and chemoresistance and may serve as a novel diagnostic biomarker or therapeutic target for breast cancer.

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“…Aberrant BMP7 expression during tumour progression has been reported in a few cancer types, including colorectal cancer, breast cancer, melanoma, and prostate cancer (12,15,18,(21)(22)(23)(24)(25)(26). High levels of BMP7 have been detected in bone metastasis of prostate cancer, and breast carcinoma as they progress to a more aggressive phenotype (3,4,9,15). Upregulation of BMP7 expression in metastatic cells has been suggested to be a critical component of osteoblastic lesion development.…”

Section: Discussionmentioning

confidence: 99%

“…Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1)(2)(3)(4)(5)(6)(7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8)(9)(10)(11)(12). The Smad-dependent signaling pathway has been proven to be the canonical pathway for BMP function (13).…”

Section: Introductionmentioning

confidence: 99%

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

et al. 2012

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Abstract. The aim of this study was to investigate the expression of bone morphogenetic protein 7 (BMP7), in human pulmonary cancer tissues/cells and to evaluate the cellular impact of bone morphogenetic proteins on pulmonary cancer cells. BMP7 expression was determined in human lung cancer cell lines. The invasiveness and growth of cells transfected with BMP7, in vitro, were evaluated using the in vitro invasion assay and in vitro tumour models. Cellular migration was analysed using wounding assays. BMP7-positive tumours correlated with the absence of bone metastasis (P=0.040). In this analysis, we identified that 4 of 4 small cell lung cancer (SCLC) tissue specimens had no BMP7 expression, which illustrated that BMP7 may have no role in SCLC. BMP7 expression was not correlated with the overall survival time in lung cancer patients. Downregulation of BMP7 expression significantly inhibited the invasiveness of SPC-A1 cells (P<0.001) and forced-expression of BMP7 dramatically increased the motility of A549 cells. Overexpression of BMP7 in A549 cells and its knockdown in SPC-A1 cells did not significantly alter proliferation compared with the control cells (P>0.5 respectively). In conclusion, we have demonstrated that BMP7 has an important role in controlling lung cancer cell motility and invasiveness, without affecting the growth process, cell proliferation and cell apoptosis. A higher BMP7 expression may be an indicator for bone metastasis. The therapeutic role of BMP7 warrants further investigation. IntroductionLung cancer is one of the most fatal tumours worldwide. Distant metastasis is an important cause for the poor prognosis. Of the factors related to metastasis, bone morphogenetic proteins (BMPs) have been recently shown to regulate the aggressiveness of cancer cells (1-7). BMPs are multifunctional signaling molecules belonging to the transforming growth factor-β (TGF-β) superfamily, which play important roles in multiple cellular processes such as cell growth, differentiation, migration and apoptosis in various types of cancer (8-12). The Smad-dependent signaling pathway has been proven to be the canonical pathway for BMP function (13). In lung cancer, expression of the BMP family members has also been reported (1,14). For example, BMP2 protein could stimulate growth, migration and invasion of lung cancer cells, and is overexpressed in virtually all types of lung cancers, including non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). Silencing of BMP3b expression during NSCLC development has been reported and the BMP3b promoter has been found to be methylated. Activation of the BMP4 signaling pathway negatively regulates the growth, and induces senescence of A549 lung adenocarcinoma cells. Thus, there may be a contrasting response to any given BMP, depending on the tumour and cell type. Despite the discordant results defining the specific effects of BMP7 in various types of cancer, published data underscore the important role that BMP7 plays in tumour development and metastasis. The expre...

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Bone morphogenetic protein 6 (BMP6) and BMP7 inhibit estrogen-induced proliferation of breast cancer cells by suppressing p38 mitogen-activated protein kinase activation

Cited by 68 publications

References 61 publications

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Disordered hepcidin–ferroportin signaling promotes breast cancer growth

Downregulation of BMP6 enhances cell proliferation and chemoresistance via activation of the ERK signaling pathway in breast cancer

Μolecular impact of bone morphogenetic proteinï¿½7, on lung cancer cells and its clinical significance

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