Müllerian Inhibiting Substance Inhibits Breast Cancer Cell Growth through an NFκB-mediated Pathway

Segev, Dorry L.; Ha, Thanh U.; Tran, Trinh T.; Kenneally, Mary; Harkin, Paul; Jung, Mira; MacLaughlin, David T.; Donahoe, Patricia K.; Maheswaran, Shyamala

doi:10.1074/jbc.m004554200

Cited by 129 publications

(127 citation statements)

References 52 publications

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“…We recently demonstrated the presence of MIS receptors in mammary tissue and breast cancer cell lines, suggesting that the mammary gland is a likely target for MIS (6,10,11). In the rat mammary gland, expression of the MIS type II receptor is suppressed during puberty when the ductal system branches and invades the adipose stroma and during massive expansion at pregnancy and lactation, but is up-regulated during involution, a time of tissue regression (11, 12).…”

Section: Mullerian Inhibiting Substance (Mis) Inhibits Breast Cancer mentioning

confidence: 99%

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Gupta

Carey

Kawakubo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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Mullerian inhibiting substance (MIS) inhibits breast cancer cell growth in vitro.To extend the use of MIS to treat breast cancer, it is essential to test the responsiveness of mammary tumor growth to MIS in vivo. Mammary tumors arising in the C3(1) T antigen mouse model expressed the MIS type II receptor, and MIS in vitro inhibited the growth of cells derived from tumors. Administration of MIS to mice was associated with a lower number of palpable mammary tumors compared with vehicle-treated mice (P ‫؍‬ 0.048), and the mean mammary tumor weight in the MIS-treated group was significantly lower compared with the control group (P ‫؍‬ 0.029). Analysis of proliferating cell nuclear antigen (PCNA) expression and caspase-3 cleavage in tumors revealed that exposure to MIS was associated with decreased proliferation and increased apoptosis, respectively, and was not caused by a decline in T antigen expression. The effect of MIS on tumor growth was also evaluated on xenografted human breast cancer cell line MDA-MB-468, which is estrogen receptor-and retinoblastoma-negative and expresses mutant p53, and thus complements the C3(1)Tag mouse mammary tumors that do not express estrogen receptor and have functional inactivation of retinoblastoma and p53. In agreement with results observed in the transgenic mice, MIS decreased the rate of MDA-MB-468 tumor growth and the gain in mean tumor volume in severe combined immunodeficient mice compared with vehicle-treated controls (P ‫؍‬ 0.004). These results suggest that MIS can suppress the growth of mammary tumors in vivo.proliferation ͉ apoptosis ͉ simian virus 40 large T antigen M ullerian inhibiting substance (MIS) is a member of the TGF-␤ family, a class of molecules that govern a myriad of cellular processes including growth, differentiation, and apoptosis. Synthesis of MIS demonstrates a sexually dimorphic pattern and is produced by Sertoli cells of the fetal and adult testis and granulosa cells of the postnatal ovary. In male embryos, MIS causes regression of the Mullerian duct, the anlagen of the Fallopian tubes, uterus, and upper vagina (1). However, a postnatal role for MIS in males and females has yet to be defined. Signaling by MIS is propagated by binding of MIS to the MIS type II receptor, a transmembrane serine, threonine kinase expressed at high levels in the Mullerian duct, Sertoli cells, and granulosa cells of the embryonic and adult gonads and in the uterus (2-4). The MIS-bound type II receptor subsequently recruits a type I receptor. Activin-like kinase 2 (ALK2), ALK3, and ALK6 have been implicated in mediating MIS signaling in cells (5-9).We recently demonstrated the presence of MIS receptors in mammary tissue and breast cancer cell lines, suggesting that the mammary gland is a likely target for MIS (6,10,11). In the rat mammary gland, expression of the MIS type II receptor is suppressed during puberty when the ductal system branches and invades the adipose stroma and during massive expansion at pregnancy and lactation, but is up-regulated during involution, a ti...

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Section: Mullerian Inhibiting Substance (Mis) Inhibits Breast Cancer mentioning

confidence: 99%

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Gupta

Carey

Kawakubo

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…Among several NF-B-dependent genes, we focused on x-ray-inducible immediate early response factor-1 (IEX-1), which is a unique immediate-early gene that was initially identified following exposure of human squamous carcinoma cells to X-irradiation (14). Recent studies indicate that IEX-1 is implicated in apoptotic signaling and cell cycle control (15)(16)(17)(18)(19)(20)(21)(22). However, IEX-1 appears to exert apparently contradictory effects, depending on the type of cells, stimuli, and its expressed forms.…”

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confidence: 99%

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Osawa

Nagaki

Banno

et al. 2003

The Journal of Immunology

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Using a cDNA microarray analysis, we identified x-ray-inducible immediate early response factor-1 (IEX-1) as a proapoptotic gene which was induced by TNF-α and also depend on NF-κB activation in Hc human hepatocytes. In these cells only the original form of IEX-1, termed IEX-1S, but not its longer transcript IEX-1L, was expressed. Overexpression of IEX-1S resulted in promotion of TNF-α-induced apoptosis in Hc cells expressing a mutant form of IκB. This proapoptotic action can be explained by its inhibitory findings on survival signals; inhibition of TNF-α-induced activation and expression of phosphatidylinositol 3-kinase (PI3K)/Akt, and also blockage of expression of Mcl-1, an antiapoptotic Bcl-2 family member which is located downstream of Akt, was inhibited by IEX-1S. LY 294002, an inhibitor of PI3K, increased IEX-1S expression induced by TNF-α and accelerated TNF-α-induced apoptosis in IκB-treated Hc cells. Overexpression of the dominant-negative Akt enhanced, but the constitutively active Akt suppressed, TNF-α-induced IEX-1S expression, suggesting that PI3K/Akt negatively regulated IEX-1S expression. These results demonstrate that NF-κB-dependent recruitment of IEX-1S may play a proapoptotic role in TNF-α-stimulated hepatocytes through blockage of the PI3K/Akt pathway. Moreover, the reciprocal cross-talk between IEX-1S and PI3K/Akt may closely be involved in the regulation of TNF-α-induced hepatocyte apoptosis.

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“…(10)(11)(12)(13)(16)(17)(18). IEX-1 was shown to inhibit cell proliferation in some cells, but it appeared to accelerate cell cycle progression in others (11,(19)(20)(21). It was also reported to promote apoptosis in 293 and HeLa cells under serum deprivation (20,22).…”

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confidence: 99%

Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice

Zhang

Schlossman

Edwards

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

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Susceptibility of activated T cells to apoptosis must be tightly regulated to ensure sufficient T cell progeny for an effective response, while allowing a rapid depletion of them at the end of the immune response. We show here that a previously isolated, NF-B͞rel target gene IEX-1 (Immediate Early response gene X-1) is highly expressed in T cells at early stages of activation, but declines with a prolonged period of activation time, coincident with an increased susceptibility of T cells to apoptosis during the late phases of an immune response. Transgenic expression of IEX-1 specifically in lymphocytes impaired apoptosis in activated T cells, extended a duration of an effectorphase of a specific immune response, and increased the accumulation of effector͞memory-like T cells and the susceptibility to a lupus-like autoimmune disease. Our study demonstrated an antiapoptotic effect of IEX-1 on T cell apoptosis triggered by ligation of Fas and T cell receptor (TCR)͞CD3 complex. The ability of extending life expectancy of T effectors, in line with a decrease in its expression following prolonged T cell activation, suggests a key role for IEX-1 in regulating T cell homeostasis during immune responses.antiapoptosis ͉ autoimmunity ͉ NF-B ͉ T cells I mmune responses are initiated when resting T cells are triggered by antigen͞MHC complexes to undergo clonal expansion and differentiation into effector populations. This response is followed by a rapid depletion of T effectors through apoptotic pathways to reduce the risk of autoimmunity (1-3). Therefore, lifespans of T effectors are critical not only in determining the duration of an immune response, but also in preventing from autoimmunity. Compelling evidence suggests that NF-B͞rel transcription factors play a pivotal role in linking between an innate and an adaptive immune response (4). However, the underlying mechanisms are not completely understood, one of which may be to extend the lifespan of T effectors by activation of NF-B͞rel transcription factors as a result of copious proinflammatory cytokines released during innate immune responses (5). In support, considerable studies indicate that activation of NF-B͞rel transcription factors promotes the survival of a variety of cells both in vitro and in vivo (6-9).IEX-1 (Immediate Early response gene X-1), also named IER3, p22͞PRG1, Dif-2, or mouse homology gly96, was isolated by several groups, but its function remains controversial (10-13). IEX-1 is a NF-B͞rel target gene and its promoter region contains a regulation site for NF-B transcription factor (14, 15). It can be rapidly up-regulated by various activators of the NF-B͞rel transcription factors such as TNF-␣, IL-1␤, PMA (phorbol 12-myristate 13-acetate), growth factors, viral infection, lipopolysaccharide (LPS), irradiation, etc. (10-13, 16-18). IEX-1 was shown to inhibit cell proliferation in some cells, but it appeared to accelerate cell cycle progression in others (11,(19)(20)(21). It was also reported to promote apoptosis in 293 and HeLa cells under serum depriv...

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Müllerian Inhibiting Substance Inhibits Breast Cancer Cell Growth through an NFκB-mediated Pathway

Cited by 129 publications

References 52 publications

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Mullerian inhibiting substance suppresses tumor growth in the C3(1)T antigen transgenic mouse mammary carcinoma model

Expression of the NF-κB Target Gene X-Ray-Inducible Immediate Early Response Factor-1 Short Enhances TNF-α-Induced Hepatocyte Apoptosis by Inhibiting Akt Activation

Impaired apoptosis, extended duration of immune responses, and a lupus-like autoimmune disease in IEX-1-transgenic mice

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