Mullerian-inhibiting substance regulates NF–κB signaling in the prostate<i>in vitro</i>and<i>in vivo</i>

Segev, Dorry L.; Hoshiya, Yasunori; Hoshiya, Makiko; Tran, Trinh T.; Carey, Jennifer; Stephen, Antonia E.; MacLaughlin, David T.; Donahoe, Patricia K.; Maheswaran, Shyamala

doi:10.1073/pnas.221599298

Cited by 71 publications

(68 citation statements)

References 48 publications

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“…Therefore, it is important to survey a large number of cervical cancer cell lines for sensitivity to MIS and to anticipate alternative mechanistic pathways of MIS response. Such is the case observed in human breast and prostate cancer cell lines in which the NF B pathway mediates MIS responsiveness (31)(32)(33).…”

Section: Mis Inhibits the Growth Of Ovarian Cancer Cells In Vitro Andmentioning

confidence: 71%

Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

Barbie

MacLaughlin

et al. 2003

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

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In addition to causing regression of the Mullerian duct in the male embryo, Mullerian Inhibiting Substance (MIS) inhibits the growth of epithelial ovarian cancer cells, which are known to be of Mullerian origin. Because the uterine cervix is derived from the same Mullerian duct precursor as the epithelium of the ovary, we tested the hypothesis that cervical cancer cells might also respond to MIS. A number of cervical cancer cell lines express the MIS type II receptor, and MIS inhibits the growth of both human papilloma virus-transformed and non-human papilloma virus-transformed cervical cell lines, with a more dramatic effect seen in the latter. As in the ovarian cancer cell line OVCAR8, suppression of growth of the C33A cervical cancer cell line by MIS is associated with induction of the p16 tumor suppressor protein. However, in contrast to OVCAR8 cells, induction of p130 and p107 appears to play an important role in the inhibition of growth of C33A cells by MIS. Finally, normal cervical tissue expresses the MIS type II receptor in vivo, supporting the idea that MIS could be a targeted therapy for cervical cancer.M ullerian Inhibiting Substance (MIS), also known as antiMullerian hormone, has long been known for its canonical activity of causing the regression of the embryonic Mullerian duct, the anlagen of the fallopian tubes, the surface epithelium of the ovaries, the uterus, the cervix, and the upper third of the vagina. Given the sensitivity of these tissues to MIS, we proposed that this 140-kDa hormone could inhibit the growth of Mullerian ductderived tumors and demonstrated that partially purified preparations of bovine MIS inhibited growth of an ovarian cancer cell line (1, 2) and of primary ovarian and endometrial cells in vitro (3, 4). Using more highly purified recombinant human MIS, we demonstrated growth inhibition of both human ovarian cancer cell lines and primary tumors in vitro and in vivo (5-8). Recently, we showed that the epithelial ovarian cancer cell line OVCAR8 expresses the MIS type II receptor and responds to MIS by growth inhibition mediated through a retinoblastoma protein (pRB)-independent mechanism involving the up-regulation of p16 (6). As a member of the INK4 family of cyclin-dependent kinase (CDK) inhibitors, p16 regulates the cell cycle by inhibiting the kinase activity of cyclin͞ CDK (CDK 4͞6) complexes (9), and induction of p16 is known to disrupt cell cycle progression and to regulate apoptosis (10-14).To study whether other Mullerian duct-derived tumors might be sensitive to MIS, we investigated its effect on human cervical cancer cell lines. The third most common neoplasm of the female genital tract, cervical cancer accounts for Ϸ10% of all cancers in women and resulted in 4,800 deaths in 1999 in the United States (15). A significant proportion of these cancers are due to infection with high risk subtypes of the human papilloma virus (HPV) (16). Despite a significant reduction in the annual cervical cancer death rate in the United States since the introduction of the Papanico...

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Section: Mis Inhibits the Growth Of Ovarian Cancer Cells In Vitro Andmentioning

confidence: 71%

Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

Barbie

MacLaughlin

et al. 2003

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

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“…Moreover, the expression of MIS receptors in nongonadal tissues such as the mammary and prostate glands (10)(11)(12)27) suggests additional functions for this hormone besides the induction of apoptotic regression of the Mullerian duct. We had demonstrated that MIS inhibits breast cancer cell growth in vitro by preventing cell cycle progression and inducing apoptosis (10).…”

Section: Discussionmentioning

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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“…Northern blot analysis of RNA isolated from T47D cells confirmed the induction of BTG2 by MIS (Figure 1a). Since we had previously demonstrated that MIS induces NF-kB DNA binding activity (Segev et al, , 2001(Segev et al, , 2002, and the BTG2 promoter is reported to have an NF-kB consensus DNA binding element (Duriez et al, 2002), we tested whether stimulation of BTG2 by MIS was mediated through activation of the NF-kB pathway. As shown in Figure 1a, upregulation of BTG2 mRNA by MIS was mitigated by the expression of dominant-negative IkB-a, suggesting that activation of the NF-kB pathway was required for this process ( Figure 1a).…”

Section: Activation Of Nf-kb Induces Btg2 Expression In Breast Cancermentioning

confidence: 99%

Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

et al. 2004

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BTG2, a p53-inducible antiproliferative gene, is stimulated in breast cancer cells by activation of nuclear factor kappa B (NF-jB). In rat mammary glands, BTG2 is expressed in epithelial cells and levels decreased during pregnancy and lactation but recovered during involution. Estrogen and progestin suppress BTG2 expression, suggesting that these steroids, which stimulate proliferation and lobuloalveolar development of mammary epithelial cells, may downregulate BTG2 in the mammary gland during pregnancy. Consistent with the report that BTG2 inhibits cyclin D1 expression, suppression of BTG2 mRNA in the mammary gland during gestation, and by estrogen and progestin, correlated with stimulation of cyclin D1. Ectopic expression of BTG2 inhibited breast cancer cell growth by arresting cells in the G1 phase, an effect reversed by cyclin D1. BTG2 expression was very low or undetectable in human breast cancer cell lines compared with nontumorigenic mammary epithelial cells, and nuclear expression of BTG2 was absent in 65% of human breast tumors compared with adjacent matched normal glands. Spontaneous mammary tumors arising in a mouse model with targeted expression of the early region of the SV40 large tumor Ag demonstrated loss of BTG2 protein very early during the tumorigenic process. Thus deregulation of BTG2 may be an important step in the development of mammary tumors.

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Mullerian-inhibiting substance regulates NF–κB signaling in the prostatein vitroandin vivo

Cited by 71 publications

References 48 publications

Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

Mullerian Inhibiting Substance inhibits cervical cancer cell growth via a pathway involving p130 and p107

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

Expression of the NF-κB-responsive gene BTG2 is aberrantly regulated in breast cancer

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