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Departments of1 , Cancer and Thoracic Surgery2 Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Okayama City 700-8558, Japan
(Correspondence should be addressed to F Otsuka; Email: fumiotsu{at}md.okayama-u.ac.jp)
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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There has been accumulating evidence that breast cancer tissue expresses all enzymes required for the local biosynthesis of estrogen from circulating precursors (Foster 2008). Two principal pathways are implicated in the last steps of estradiol formation in breast cancer tissues, including the aromatase pathway that transforms androgens into estrogens and the sulfatase pathway that converts estrone sulfate into estrone. The final step of the estrogen steroidogenesis is conversion of weak estrone to biologically active estradiol by actions of a reductive 17β-hydroxysteroid dehydrogenase type 1. A recent study has suggested that estron sulfate via sulfatase is a much more likely precursor for estradiol than androgens via aromatase in human breast tumors (James et al. 2001, Pasqualini & Chetrite 2005, Stanway et al. 2007). It is also well established that steroid sulfo-transferases, which convert biologically active estrogens into their inactive sulfates, are also present in breast cancer tissues (Falany & Falany 1996). Therefore, therapeutic targets for breast cancers include not only the binding of estrogen to ER but also the activity of estrogenic enzymes in the tumor tissues (Pasqualini 2004, Sasano et al. 2006, Subramanian et al. 2008).
Bone morphogenetic proteins (BMPs) that belong to transforming growth factor (TGF)-β superfamily have been widely recognized as important molecules involved in tissue differentiation and functional modulation of various endocrine systems (Simic & Vukicevic 2005). BMPs were originally identified as the active components in bone extracts capable of inducing bone formation at ectopic sites. Recently, a variety of physiological BMP actions in many endocrine tissues including the ovary (Otsuka et al. 2000, Shimasaki et al. 2004), pituitary (Otsuka & Shimasaki 2002), thyroid (Suzuki et al. 2005), and adrenal (Suzuki et al. 2004, Kano et al. 2005, Inagaki et al. 2006) have been clarified. BMPs have been paid attention for the possible link with tumorigenesis, considering the BMP action as regulators of cell proliferation and differentiation (Otani et al. 2007). Since BMPs constitute an important signaling pathway in the bone, the possible link with establishment of metastatic lesion in the bone has been postulated.
Recent studies have demonstrated the presence of the TGF-β signaling pathway in mammary cells and its importance in maintaining the growth state of these cells. There have been several reports showing the expression of some of TGF-β superfamily proteins, such as BMP2 (Arnold et al. 1999, Raida et al. 2005), BMP6 (Clement et al. 1999), and BMP7 (Schwalbe et al. 2003, Alarmo et al. 2006), in breast cancer cells, in which their possible role in breast cancer development and involvement in bone metastasis has been discussed (Pouliot & Labrie 2002, Bobinac et al. 2005, Clement et al. 2005). Furthermore, the involvement of BMP–SMAD activation in the progression and dedifferentiation of ER-positive breast cancer was recently reported (Helms et al. 2005). However, the pathophysiologic significance of BMP system in breast cancer remains poorly understood. In the present study, we investigated the effects of BMPs on breast cancer cell proliferation evoked by estrogen using a human breast cancer cell line. Here, we uncovered the antagonistic effects of BMP on estrogen-induced mitosis of breast cancer cells through the functional interrelationship between ER and BMP signaling.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Dulbecco's Modified Eagle's Medium (DMEM), penicillin–streptomycin solution, 17β-estradiol, BSA-conjugated 17β-estradiol (estradiol–BSA), and human recombinant activin A were purchased from Sigma–Aldrich Co. Ltd. Recombinant human BMP2, BMP4, BMP6, and BMP7 were purchased from R&D Systems, Inc. (Minneapolis, MN, USA), and U0126, SB203580, and LY294002 were from Promega Corp. SP600125 was from Biomol Lab. Inc. (Plymouth Meeting, PA, USA) and SH-5 was from Calbiochem (San Diego, CA, USA). Plasmids of Id-1-Luc were kindly provided from Drs Tetsuro Watabe and Kohei Miyazono, Tokyo University, Japan.
Breast cancer cell culture
The human breast cancer cell line, MCF-7, was from American Type Culture Collection (Manassas, VA, USA). MCF-7 cells were cultured in DMEM supplemented with 10% fetal calf serum (FCS) and penicillin–streptomycin solution at 37 °C under a humid atmosphere of 95% air/5% CO2. In some experiments, cell numbers were counted by culturing MCF-7 cells in 12-well plates (1x105 viable cells) with serum-free DMEM for 24 h. The cells were then washed with PBS, trypsinized, and applied for a coulter counter (Beckman Coulter Inc., Fullerton, CA, USA). Changes in cell morphology and cell viability were monitored using an inverted microscope.
RNA extraction, RT-PCR, and quantitative real-time PCR analysis
To prepare total cellular RNA, MCF-7 cells were cultured in 12-well plate (5x105 viable cells) and treated with indicated concentrations of estradiol and growth factors including BMPs in serum-free DMEM. After 24-h culture, the medium was removed, and total cellular RNA was extracted using TRIzol (Invitrogen Corp.), quantified by measuring absorbance at 260 nm, and stored at –80 °C until assay. The expression of BMP receptors, follistatin, SMADs, ESR1, ESR2, aromatase, and steroid sulfatase mRNAs were detected by RT-PCR analysis. The extracted RNA (1.0 µg) was subjected to an RT reaction using the First-strand cDNA synthesis system (Invitrogen Corp.) with random hexamer (2 ng/µl), reverse transcriptase (200 U), and deoxynucleotide triphosphate (0.5 mM) at 42 °C for 50 min and 70 °C for 10 min. Subsequently, hot-start PCR was performed using MgCl2 (1.5 mM), deoxynucleotide triphosphate (0.2 mM), and 2.5 U of Taq DNA polymerase (Invitrogen Corp). Oligonucleotides used for RT-PCR were custom-ordered from Invitrogen Corp. PCR primer pairs were selected from different exons of the corresponding genes as follows: ESR1, 1393–1413 and 1632–1652 (from GenBank accession #NM_000125); ESR2, 395–415 and 589–609 (from AB006590); aromatase, 914–934 and 1235–1256 (from M22246); steroid sulfatase, 513–533 and 693–713 (from NM_000351); and a house-keeping gene, ribosomal protein L19 (RPL19; Szabo et al. 2004), 401–420 and 571–590 (from NM_000981). PCR primer pairs for ACVR1, BMPR1A, ACVR1B, BMPR1B, activin type II receptor (ACVR2A), ACVR2B, BMP type II receptor (BMPRII), follistatin, SMAD1–8, and BMP6 and BMP7 were individually selected for regular PCR and real-time PCR, as previously reported (Takeda et al. 2003, Miyoshi et al. 2006, Inagaki et al. 2007). Aliquots of PCR products were electrophoresed on 1.5% agarose gels and visualized after ethidium bromide staining. For the quantification of ESR1, ESR2, aromatase, steroid sulfatase, ACVR1, BMPR1A, BMPR1B, ACVR2A, ACVR2B, BMPRII, BMP6, and BMP7 mRNA levels, real-time PCR was performed using LightCycler-FastStart DNA Master SYBR Green I system (Roche Diagnostic Co.) under conditions of annealing at 60–62 °C with 4 mM MgCl2, following the manufacturer's protocol. Accumulated levels of fluorescence were analyzed by the second derivative method after the melting curve analysis for each PCR product (Roche Diagnostic), and then the expression levels of target genes were standardized by RPL19 level in each sample.
Thymidine incorporation assay
MCF-7 cells (1x104 viable cells) were precultured in 12-well plates with DMEM containing 10% FCS for 24 h. After preculture medium was replaced with fresh serum-free medium and indicated combinations of estradiol, estradiol–BSA, mitogen-activated protein kinase (MAPK) inhibitors, phosphatidylinositol 3-kinases (PI3K)/AKT inhibitors, and growth factors including BMPs and activin were added to the culture medium. For the experiments using estradiol–BSA, the preparation of estradiol–BSA free of estadiol was performed as follows: 4 ml estradiol–BSA (1.25 mM in estrogen dissolved in 50 mM Tris–HCl (pH 8.5)) was added to a centrifugal Amicon Ultra filter unit with a MW cut-off of 5000 (Millipore, Bedford, MA, USA) and centrifuged at 4000 g until 50 µl retentate remained. The retentate was washed with Tris buffer and final volume was adjusted to 5 ml (1 mM). After 24-h culture, 0.5 µCi/ml [methyl-3H]thymidine (Amersham Pharmacia) was added, and incubated for 3 h at 37 °C. The incorporated thymidine was detected, as we previously reported (Takeda et al. 2004). Cells were then washed with PBS, incubated with 10% ice-cold trichloroacetic acid for 60 min at 4 °C, and solubilized in 0.5 M NaOH, and radioactivity was determined with a liquid scintillation counter (TRI-CARB 2300TR, Packard Co., Meriden, CT, USA).
Western immunoblot analysis
Cells (1x105 viable cells) were precultured in 12-well plates in DMEM containing 10% FCS for 24 h. After preculture, medium was replaced with serum-free fresh medium, and then indicated concentrations of estradiol and growth factors including BMPs and activin were added to the culture medium. After stimulation with hormones or growth factors for indicated periods, cells were solubilized in 100 µl RIPA lysis buffer (Upstate Biotechnology, Inc., Lake Placid, NY, USA) containing 1 mM Na3VO4, 1 mM sodium fluoride, 2% SDS, and 4% β-mercaptoethanol. The cell lysates were then subjected to SDS-PAGE/immunoblotting analysis as we reported earlier (Otani et al. 2007), using anti-phospho- and anti-total-extracellular signal-regulated kinase (ERK) 1/2 MAPK antibody (Cell Signaling Technology, Inc., Beverly, MA, USA), anti-phospho- and anti-total-p38 MAPK antibody (Cell Signaling Technology, Inc.), anti-phospho- and anti-total-stress-activated protein kinase/c-Jun NH2-terminal kinase (SAPK/JNK) MAPK antibody (Cell Signaling Technology, Inc.), anti-phospho-SMAD1,5,8 (pSMAD1,5,8) antibody (Cell Signaling Technology, Inc.), anti-steroid sulfatase antibody (Abcam Inc., Cambridge, MA, USA), and anti-actin antibody (Sigma–Aldrich Co. Ltd).
Immunofluorescence microscopy
Cells were precultured in serum-free DMEM using chamber slides (Nalge Nunc Int., Naperville, IL, USA) for 24 h. Cells at 
40% confluency were pretreated with estradiol (100 nM) for 1 h and then treated with BMP6 and BMP7 (100 ng/ml) for 1 h. After the stimulation, cells were fixed with 4% formaldehyde in PBS, permeabilized with 0.5% Triton X-100 in PBS at room temperature, and washed three times with PBS. The cells were then incubated with anti-phospho-SMAD1,5,8 antibody for 1 h and washed three times with PBS, then with AlexaFlour-488 anti-rabbit IgG (Invitrogen Corp.) in humidified chamber for 1 h and washed with PBS, followed by application of the counter medium containing 4',6'-diaminodino-2-phenylindole (Invitorogen Corp.), and then stained cells were visualized under a fluorescent microscope.
Transient transfection and luciferase assay
Cells (1x104 viable cells) were precultured in 12-well plates in DMEM with 10% FCS for 24 h. The cells were then transiently transfected with 500 ng Id-1-Luc reporter plasmid and 50 ng cytomegalovirus-β-galactosidase (β-gal) plasmid (pCMV-β-gal) using FuGENE 6 (Roche Molecular Biochemicals) for 24 h. The cells were then treated with BMP2, BMP4, BMP6, and BMP7 in combination with estradiol in serum-free fresh medium for 24 h. The cells were washed with PBS and lysed with Cell Culture Lysis Reagent (Toyobo, Osaka, Japan). Luciferase activity and β-gal activity of the cell lysate were measured by luminescencer-PSN (ATTO, Tokyo, Japan), as we previously reported (Miyoshi et al. 2006). The data were shown as the ratio of luciferase to β-gal activity.
cDNA array analysis
Oligo GEArray system (SuperArray Bioscience Corp., Frederick, MD, USA) that includes 113 genes of human TGF-β and BMP signaling pathway was used for analyzing the expression pattern of BMP signaling system in MCF-7 cells. As we previously reported (Miyoshi et al. 2006, Yamashita et al. 2008), extracted total RNAs (2.0 µg) were used as templates to generate biotin-16-dUTP-labeled cDNA probes according to the manufacture's instruction. The cDNA probes were denatured and hybridized at 60 °C with the cDNA array membranes, which were washed and exposed to X-ray films with use of chemiluminescent substrates. To analyze the array results, we scanned the X-ray film and the image was inverted as grayscale TIFF files. The spots were digitized and analyzed using GEArray analyzer software (SuperArray Bioscience Corp.) and the data were normalized by subtraction of the background as the average intensity levels of three spots containing plasmid DNA of pUC18. The spots of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) and cyclophilin A (PPIA) were used as positive controls to compare the membranes. Using these standardized data, we compared the signal intensity of the membranes using the GEArray analyzer program (SuperArray Bioscience Corp).
Statistical analysis
All results are shown as mean±S.E.M. of data from at least three separate experiments, each performed with triplicate samples. Differences between groups were analyzed for statistical significance using ANOVA with Fisher's protected least significant difference test (StatView 5.0 software, Abacus Concepts, Inc., Berkeley, CA, USA). P values <0.05 were accepted as statistically significant.
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We next investigated the expression changes of ER in MCF-7 cells under the influence of estradiol and BMP/activin. Estradiol exposure (1–100 nM) for 24 h reduced mRNA levels of ESR1 in MCF-7 cells (Fig. 3A), but had no significant effects on ESR2 expression (Fig. 3B). Interestingly, activin A (100 ng/ml) significantly decreased ESR1 expression regardless of the presence or absence of estradiol (100 nM), although BMPs did not affect either mRNA levels of ESR1 or ESR2. Thus, the suppressive effect of activin A on estradiol-induced cell proliferation is likely due to the reduction of ESR1 expression.
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, activinβA, and activinβB subunits, were relatively abundant (Fig. 7B), in which BMP6, BMP7, and inhibin/activin subunits were downregulated by estradiol exposure (10 and 100 nM) in MCF-7 cells. The reduction of BMP6 and BMP7 mRNA by estradiol treatment was confirmed by real-time PCR analysis (Fig. 7C). Thus, estrogen induces a differential pattern of key BMP signaling molecules, suggesting the existence of a possible functional link between estrogen and breast cancer BMP system. The estrogen-induced reduction of BMPR1A, BMPR1B, ACVR2A, and ACVR2B expression was most likely reflected in the decreased Id-1 activation by BMP2 and BMP4 (Fig. 6A).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Several preferential combinations of BMP ligands and receptors have been recognized to date, e.g., BMP2, BMP4, and growth and differentiation factor-5 preferentially bind to BMPR1A and/or BMPR1B; BMP6, and BMP7 most readily bind to ACVR1 and/or BMPR1B (ten Dijke et al. 1994, Yamashita et al. 1995, Ebisawa et al. 1999, Aoki et al. 2001), and BMP15 efficiently binds to BMPR1B with much lower affinity for BMPR1A (Moore et al. 2003). Regarding type II receptors, ACVR2A act as receptors not only for activin but also BMP6 and BMP7 (Yamashita et al. 1995, Ebisawa et al. 1999), while BMPRII binds exclusively to BMP2, BMP4, BMP6, BMP7, and BMP15 (it does not bind activin; Liu et al. 1995, Nohno et al. 1995, Rosenzweig et al. 1995, Moore et al. 2003). Pouliot et al. (2003) reported that BMPRII plays a key role in breast cancer cell proliferation based on the experiments using dominant-negative BMPRII constructs. Helms et al. (2005) demonstrated that the expression of BMPR1B is a major hallmark of progression and prognosis of ER-positive breast cancer. Among the BMP ligands tested, our present data showed that BMP6 and BMP7 exerted effective activation of BMP–SMAD signaling and mitotic inhibition of estrogen-treated MCF-7 cells. Since BMPR1A, BMPR1B, ACVR2A, and ACVR2B expression was decreased by estradiol, ACVR1, and BMPRII are the major functional complex for BMP system, which leads to the sustained action of BMP6 and BMP7 in estrogen-exposed MCF-7 cells.
The expression pattern of BMP system in estrogen-treated MCF-7 cells also reflected the inhibitory effects of BMPs on MAPK phosphorylation. BMP6 and BMP7 preferentially inhibited estradiol-induced phosphorylation of p38 pathway although estradiol activated MAPK signaling including ERK1/ERK2, p38, and SAPK/JNK pathways. The activity and/or expression of AKT pathway, a central effector for many signaling pathways involving ER, ERBB2, and epidermal growth factor receptor, is generally amplified in breast cancer cells (Dillon et al. 2007, Liu et al. 2007). It is also known that high activity of AKT in breast cancer is associated with poor prognosis, pathological phenotype, and hormone and chemotherapeutic resistance (Liu et al. 2007). In contrast to the effects of SB203580 on MCF-7 mitosis, the inhibition of PI3K–AKT pathway is functionally linked to basal cell proliferation rather than estrogen-induced cell proliferation by MCF-7 cells. Given that SB203580, but not U0126 and SP600125, suppressed estradiol-induced cell mitosis, p38 pathway appeared to be a critical signaling for breast cancer cell proliferation in the presence of estrogen.
There has been accumulating evidence that estradiol activates gene expression without direct DNA binding by ER (Biswas et al. 2005). The nongenomic actions of estradiol include effects on calcium flux that occur rapidly without being mediated by transcriptional effects of nuclear ER (Nadal et al. 2001, Song et al. 2002, Gaben et al. 2004). Based on the rapid activation of estrogen-induced MAPK phosphorylation including ERK, p38, and SAPK/JNK pathways, nongenomic effects should be involved in the signal activation in MCF-7 cells. BSA-conjugated estradiol, which cannot bind to nuclear ER (Taguchi et al. 2004), also induced MCF-7 cell mitosis although the effects were less potent than those induced by unbound estradiol. Taken together, nongenomic effects of estradiol are also involved, at least in part, in the estrogen induction of cell proliferation. Immunoreactive ER antigen was reportedly detected on the surface of both naturally ER-positive cells and in cells transfected with ER expression constructs (Watson et al. 2002). ER-transfected cells also resulted in detectable membrane ER, in which estradiol mediates MAPK action, activation of the cAMP, and inositol–triphosphate pathways (Razandi et al. 1999). Considering that BMPs have also been shown to signal via the p38 class of MAPK in some cell types (Iwasaki et al. 1999, Lee et al. 2002), a functional crosstalk may exist between the breast cancer BMP system, ER signal, and MAPK pathway. In this regard, Yamamoto et al. (2002) reported that estrogen inhibition on BMP2-induced SMAD signaling was due to the direct physical interaction between SMADs and ER in MCF-7 cells. Further study would be needed to elucidate the molecular mechanism by which BMPs antagonize the MAPK activation through genomic and/or nongenomic actions induced by estrogen.
The modulation of ER expression may also be involved in the mechanism by which estrogen stimulates breast cancer cell proliferation. In the present study, we found that ESR1 expression was not only autoregulated by estradiol but also controlled by activin. Inhibitory effect of activin on MCF-7 cell mitosis could be partly due to the reduction of ESR1 expression. It was also notable that activin inhibited estradiol-induced phosphorylation of p38 MAPK signaling, which was similar to the effects elicited by BMP6 and BMP7. Thus, activin possibly plays an inhibitory role in estrogen-induced MCF-7 cell mitosis by reducing ESR1 expression as well as by inhibiting estrogen-induced MAPK phosphorylation. Estrogen exerts biologic actions, including broad changes in gene expression, through nuclear proteins called ER, which now include two subtypes, ESR1 and ESR2 (Nilsson et al. 2001). ESR1 is detectable in 40–70% of breast tumors and the presence of ESR1 protein has been a standard criterion for adjuvant therapy with antiestrogens that antagonize ER function and/or aromatase inhibitors (Shupnik 2007). In contrast, the roles of ESR2 have been obscure in the breast cancer tumorigenesis. ESR1 and ESR2 are structurally similar having high homology within the DNA and hormone-binding domains at 95 and 53% respectively (Keen & Davidson 2003). Although this domain-specific homology suggests that ESR1 and ESR2 are likely to share similar DNA and ligand-binding function, the low overall homology at 30% may indicate the global difference of their function. In the present study, the change of ESR2 mRNA was not clearly detected by BMP/activin treatments regardless of estrogen action. Given the finding that the presence of ESR2 can be an indicator for therapeutic responses in ESR1-positive tumors (Lin et al. 2007), ESR2 may act by antagonizing ESR1 on a specific subset of estrogen-stimulated genes, leading to the evasion of ESR1-stimulated cell growth.
In addition to the control of ER signaling, the regulation of estrogenic enzymes is effective to control the growth of breast cancer (Subramanian et al. 2008, Foster 2008). It has been widely accepted that breast tumors can synthesize 17β-estradiol from adrenal androgen precursors. This occurs through the aromatization of androstenedione to estrone by aromatase, followed by the conversion of estrone to 17β-estradiol by 17β-hydroxysteroid dehydrogenase type 1 (Pasqualini 2004, Foster 2008). Breast cancer cells express both steroid sulfotransferase and steroid sulfatase activities, the latter of which can release estrone from estrone sulfate peripherally synthesized in adipose tissues. Pasqualini & Chetrite (2001) estimated that steroid sulfatase activity is by far greater than aromatase activity in both premenopausal and postmenopausal breast tumors. In our study, estrogen exposure downregulated not only ESR1 expression but also reduced steroid sulfatase expression in MCF-7 cells. Since steroid sulfatase activity contributes to accumulation of intra-tumor 17β-estradiol, the expression level of steroid sulfatase can be a critical factor to estimate the growth activity of breast cancer. In the present study, BMP6 and BMP7 efficaciously suppressed steroid sulfatase expression in MCF-7 cells at mRNA and protein levels. However, the reduction of steroid sulfatase expression by BMPs was not directly reflected to the basal MCF-7 cell proliferation in serum-free conditions. Given that steroid sulfatase inhibitors are effective for inhibiting MCF-7 cell proliferation induced by estrone sulfate, i.e. a substrate for steroid sulfatase (Selcer et al. 1997, Rasmussen et al. 2007), the effects of BMP6 and BMP7 on steroid sulfatase expression may also contribute to the inhibition of estrogen-sensitive breast cancer cell proliferation.
Collectively, BMP6 and BMP7 antagonize estrogen-induced breast cancer cell proliferation through inhibiting p38 phosphorylation as well as estrogenic enzyme expression. These results suggest the existence of a novel functional crosstalk between the BMP system and estrogen signaling through MAPK in breast cancer cells. On the other hand, estrogen altered the BMP–SMAD signaling by downregulating specific BMP receptor expression in breast cancer cells. The inhibitory effects of BMP/activin on MAPK pathway and/or the expression of ER and estrogenic enzymes are most likely involved in the suppression of estrogen-induced mitosis of breast cancer cells.
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Declaration of interest |
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Acknowledgements |
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDeclaration of interestReferences |
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Received in final form 19 August 2008
Accepted 9 September 2008
Made available online as an Accepted Preprint 9 September 2008
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