Mullerian Inhibiting Substance Promotes Interferon γ-induced Gene Expression and Apoptosis in Breast Cancer Cells

Hoshiya, Yasunori; Gupta, Vandana; Kawakubo, Hirofumi; Brachtel, Elena F.; Carey, Jennifer; Sasur, Laura M.; Scott, A. I.; Donahoe, Patricia K.; Maheswaran, Shyamala

doi:10.1074/jbc.m307626200

Cited by 32 publications

(37 citation statements)

References 49 publications

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“…This finding is not completely unexpected. Recent reports have highlighted the ability of IRF-1 to mediate growth arrest and apoptosis in breast cancer cell lines (Kim et al, 2002(Kim et al, , 2004Hoshiya et al, 2003). In addition, evidence suggests that IRF-1 plays a role in mammary homeostasis, as IRF-1 is critical for mammary gland involution and loss of expression of IRF-1 is an early event in mammary carcinogenesis (Doherty et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

“…Specifically, IRF-1 promotes apoptosis associated with caspase-1 activation (Tamura et al, 1995;Romeo et al, 2002). More recently, IRF-1 has been shown to be a tumor suppressor and critical for mammary gland involution (Yim et al, 1997;Nozawa et al, 1999;Hoshiya et al, 2003;Kim et al, 2004). Studies have also shown that IRF-1 expression is lowered or the gene is mutated in multiple cancers, including breast cancer (Doherty et al, 2001;Tzoanopoulos et al, 2002).…”

Section: Introductionmentioning

confidence: 97%

“…IRF-1 is a transcriptional regulator that has been shown to promote apoptosis following DNA damage and is critical for mammary gland involution (Kroger et al, 2002;Hoshiya et al, 2003 (Figure 2a and b). IRF-1 protein induction was first observed at 30 min (1.5-fold, P-value o0.025) and was maximally induced at 3 h (2.3-fold, P-value o0.001) (Figure 2c and d).…”

Section: Irf-1 Is Induced By Tammentioning

confidence: 99%

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Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

et al. 2004

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Unlike estrogen receptor-positive (ER( þ )) breast cancers, normal human mammary epithelial cells (HMECs) typically express low nuclear levels of ER (ER poor). We previously demonstrated that 1.0 lM tamoxifen (Tam) promotes apoptosis in acutely damaged ER-poor HMECs through a rapid, 'nonclassic' signaling pathway. Interferon-regulatory factor-1 (IRF-1), a target of signal transducer and activator of transcription-1 transcriptional regulation, has been shown to promote apoptosis following DNA damage. Here we show that 1.0 lM Tam promotes apoptosis in acutely damaged ER-poor HMECs through IRF-1 induction and caspase-1/3 activation. Treatment of acutely damaged HMEC-E6 cells with 1.0 lM Tam resulted in recruitment of CBP to the c-IFN-activated sequence element of the IRF-1 promoter, induction of IRF-1, and sequential activation of caspase-1 and -3. The effects of Tam were blocked by expression of siRNA directed against IRF-1 and caspase-1 inhibitors. These data indicate that Tam induces apoptosis in HMEC-E6 cells through a novel IRF-1-mediated signaling pathway that results in activated caspase-1 and -3.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 97%

Section: Irf-1 Is Induced By Tammentioning

confidence: 99%

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Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

et al. 2004

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“…Comprehensive studies in our laboratory, and in those of many others, have shown that MIS downstream signal transduction pathways include MISRII (28)(29)(30), the type I receptors Alk2 (31) and Alk3 (32), Smads 1͞5͞8 (33)(34)(35), cyclin-dependent kinase inhibitors (4, 9, 10), and cytokine-inducible pathways (36)(37)(38)(39), suggesting mechanisms of action that are potentially different from those of most cytotoxic drugs.…”

Section: Ullerian Inhibiting Substance (Mis) May Have Its Most Im-mentioning

confidence: 99%

“…Biological modifiers such as MIS and chemotherapeutic drugs can function in rationally selected combinations to achieve better tumor control at decreased doses of either agent, resulting in decreased toxicity, reduced morbidity, and most importantly a wider therapeutic window (36). This will be particularly important for those agents with a significant toxicity at the clinically efficacious dose range.…”

Section: Ullerian Inhibiting Substance (Mis) May Have Its Most Im-mentioning

confidence: 99%

Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer

Pieretti-Vanmarcke¹,

Donahoe²,

Pearsall³

et al. 2006

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

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Mullerian Inhibiting Substance (MIS), a biological modifier that causes regression of Mullerian ducts in male embryos, is effective as a single agent in vitro and in vivo against human and mouse ovarian cancer cell lines expressing MIS type II receptor; however, little is known about how recombinant human MIS (rhMIS), now being scaled for preclinical trials, could be used in combination with cytotoxic or targeted chemotherapeutic agents. Mouse serous and endometrioid ovarian carcinoma cell lines were tested in vitro against rhMIS alone and with doxorubicin, paclitaxel, or cisplatin as agents in clinical use. Because MIS releases FK506 binding protein (FKBP12), which activates the mammalian target of rapamycin (mTOR) downstream of Akt, rhMIS and rapamycin combinations were tested. MIS increases p16 protein levels, and 5 -Aza-2 -deoxycytidine (AzadC) induces p16 mRNA; therefore, they were used in combination in vitro and in vivo with a human ovarian cancer cell line. A paclitaxel-resistant human ovarian cancer cell line and its parental line both respond to rhMIS in vitro. Additivity, synergy, or competition was observed with MIS and rapamycin, AzadC, doxorubicin, cisplatin, and paclitaxel, suggesting that MIS in combination with selective targeted therapies might achieve greater activity against ovarian cancer than the use of each individual agent alone. These assays and statistical analyses could be useful in selecting rhMIS and chemotherapeutic agent combinations that enhance clinical efficacy and reduce toxicity. For example, granulosa cell tumors can produce serum MIS at concentrations 1,000-fold higher (1, 2), and normal baby boys can produce MIS concentrations at least 60-fold higher, than those found in normal females (3), without apparent adverse outcomes. It is anticipated that exogenous recombinant human MIS (rhMIS) will be nontoxic as a single agent and that it can be used effectively in combination with chemotherapy drugs to lower their toxicity. We originally hypothesized that cancers of Mullerian origin that expressed MISRII could be targets for MIS treatment (4-9), focusing first on ovarian cancers because they are derived from an MISsensitive surface or coelomic epithelium (10) and have the worst prognosis of all female reproductive tumors. Furthermore, ovarian ascites cells are also accessible ex vivo to examine biomarkers that may predict their response and mechanisms of biologic effect. The idea that MIS could be used to treat epithelial ovarian cancer is predicted by the fact that the histology of the embryonic Mullerian ducts is recapitulated in the common ovarian adenocarcinomas that arise from the surface or coelomic epithelium, which in the embryo invaginates to form the Mullerian duct (11)(12)(13)(14).The discovery that abdominal ascites cells from Ͼ50% of Stage III or IV ovarian cancer patients bound rhMIS, expressed MISRII mRNA, and were inhibited by rhMIS when treated in ex vivo proliferation assays (4), makes it compelling to study MIS as a potential therapeutic agent. The availabilit...

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Circulating anti‐Müllerian hormone and breast cancer risk: A study in ten prospective cohorts

Clendenen

Afanasyeva

et al. 2018

Intl Journal of Cancer

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A strong positive association has been observed between circulating anti-Müllerian hormone (AMH), a biomarker of ovarian reserve, and breast cancer risk in three prospective studies. Confirming this association is important because of the paucity of biomarkers of breast cancer risk in premenopausal women. We conducted a consortium study including ten prospective cohorts that had collected blood from premenopausal women. A nested case-control design was implemented within each cohort. A total of 2,835 invasive (80%) and in situ (20%) breast cancer cases were individually matched to controls (n = 3,122) on age at blood donation. AMH was measured using a high sensitivity enzyme-linked immunoabsorbent assay. Conditional logistic regression was applied to the aggregated dataset. There was a statistically significant trend of increasing breast cancer risk with increasing AMH concentration (p across quartiles <0.0001) after adjusting for breast cancer risk factors. The odds ratio (OR) for breast cancer in the top vs. bottom quartile of AMH was 1.60 (95% CI = 1.31-1.94). Though the test for interaction was not statistically significant (p = 0.15), the trend was statistically significant only for tumors positive for both estrogen receptor (ER) and progesterone receptor (PR): ER+/PR+: OR = 1.96, 95% CI = 1.46-2.64, p <0.0001; ER+/PR-: OR = 0.82, 95% CI = 0.40-1.68, p = 0.51; ER-/PR+: OR = 3.23, 95% CI = 0.48-21.9, p = 0.26; ER-/PR-: OR = 1.15, 95% CI = 0.63-2.09, p = 0.60. The association was observed for both pre- (OR = 1.35, 95% CI = 1.05-1.73) and post-menopausal (OR = 1.61, 95% CI = 1.03-2.53) breast cancer (p = 0.34). In this large consortium study, we confirmed that AMH is associated with breast cancer risk, with a 60% increase in risk for women in the top vs. bottom quartile of AMH.

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Mullerian Inhibiting Substance Promotes Interferon γ-induced Gene Expression and Apoptosis in Breast Cancer Cells

Cited by 32 publications

References 49 publications

Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

Interferon-regulatory factor-1 is critical for tamoxifen-mediated apoptosis in human mammary epithelial cells

Mullerian Inhibiting Substance enhances subclinical doses of chemotherapeutic agents to inhibit human and mouse ovarian cancer

Circulating anti‐Müllerian hormone and breast cancer risk: A study in ten prospective cohorts

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