Prognostic Significance of Immunoreactive Neutrophil Elastase in Human Breast Cancer: Long-Term Follow-Up Results in 313 Patients

Akizuki, Miwa; Fukutomi, Takashi; Takasugi, M; Takahashi, Satoshi; Satō, Takashi; Harao, Michiko; Mizumoto, Takao; Yamashita, Jun‐ichi

doi:10.1593/neo.06808

Cited by 57 publications

(56 citation statements)

References 25 publications

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“…I3C acts as a specific and potent noncompetitive enzymatic inhibitor of human neutrophil elastase activity, which is highly expressed in breast cancer cells and has been shown to be a prognostic marker for reduced survival rates of primary breast cancer patients (34)(35)(36). Intracellular elastase selectively cleaves the 50-kDa cyclin E to generate several lower-molecular-weight forms of cyclin E ranging from 33 kDa to 43 kDa in size.…”

Section: Discussionmentioning

confidence: 99%

“…Of the 3 general classes of human elastases that have been characterized (pancreatic, polymorphonuclear neutrophil, and metalloelastase), high levels of neutrophil elastase have been implicated in playing a critical role in the process of tumorigenesis of human breast cancers (32,33) and other cancers including nonsmall-cell lung carcinoma (40) and bladder cancer (41). In patients, high levels of elastase expression and/or activity in breast cancer tissue can be associated with poor clinical outcome, reduced survival rates (35,36), decreased responsiveness to chemotherapy (42), and reduced responsiveness to endocrine treatment (33,34). The level of immunoreactive elastase in tumors has been shown to be an independent prognostic factor for reduced survival in patients with breast cancer who have undergone curative surgery (36).…”

Section: Discussionmentioning

confidence: 99%

“…In patients, high levels of elastase expression and/or activity in breast cancer tissue can be associated with poor clinical outcome, reduced survival rates (35,36), decreased responsiveness to chemotherapy (42), and reduced responsiveness to endocrine treatment (33,34). The level of immunoreactive elastase in tumors has been shown to be an independent prognostic factor for reduced survival in patients with breast cancer who have undergone curative surgery (36). Elastase expression in primary breast cancers was correlated with production of the hyperactive lower-molecular-weight forms of cyclin E (35), suggesting a clinically relevant direct link between elastase activity and tumor growth.…”

Section: Discussionmentioning

confidence: 99%

“…Elastase expression in primary breast cancers was correlated with production of the hyperactive lower-molecular-weight forms of cyclin E (35), suggesting a clinically relevant direct link between elastase activity and tumor growth. There are significant variations of elastase levels in the general population and in specific tissues (36). Conceivably individual differences in elastase expression and/or activity may directly contribute to variations in correlation between the intake of cruciferous vegetables and cancer risk (3) as well as susceptibility of patients to the potential therapeutic use of I3C.…”

Section: Discussionmentioning

confidence: 99%

“…Of the 3 general classes of human elastase that have been characterized [polymorphonuclear neutrophil elastase or leukocyte elastase, metalloelastase (or MMP12), and pancreatic elastase], the neutrophil elastase is highly expressed in human breast cancers and has been implicated in the processes of tumorigenesis (32). Importantly, the level and enzymatic activity of neutrophil elastase are an independent prognostic marker for breast cancer survival and clinical outcome as well as for metastasis progression of various cancers (33)(34)(35)(36). In this report, we demonstrate that the dietary phytochemical I3C is a noncompetitive inhibitor of human elastase enzymatic activity that directly accounts for the disrupted cyclin E processing in human breast cancer cells, and therefore we have identified the first functional cellular target protein for I3C that mediates the indole-induced G 1 cell-cycle arrest of human cancer cells.…”

mentioning

confidence: 99%

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The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Nguyen¹,

Aronchik²,

Brar³

et al. 2008

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

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Indole-3-carbinol (I3C), a naturally occurring component of Brassica vegetables, such as broccoli, cabbage, and Brussels sprouts, induces a G 1 cell-cycle arrest of human breast cancer cells, although the direct cellular targets that mediate this process are unknown. Treatment of highly invasive MDA-MB-231 breast cancer cells with I3C shifted the stable accumulation of cyclin E protein from the hyperactive lower-molecular-mass 35-kDa form that is associated with cancer cell proliferation and poor clinical outcomes to the 50-kDa cyclin E form that typically is expressed in normal mammary tissue. An in vitro cyclin E processing assay, in combination with zymography, demonstrated that I3C, but not its natural dimer, 3,3 -diindolylmethane, disrupts proteolytic processing of the 50-kDa cyclin E into the lower-molecular-mass forms by direct inhibition of human neutrophil elastase enzymatic activity. Analysis of elastase enzyme kinetics using either cyclin E or N-methoxysuccinyl-Ala-Ala-Pro-Val-p-nitroanalide as substrates demonstrated that I3C acts as a noncompetitive inhibitor of elastase activity with an inhibitory constant of Ϸ12 M. Finally, siRNA ablation of neutrophil elastase protein production in MDA-MB-231 cells mimicked the I3C-disrupted processing of the 50-kDa cyclin E protein and the indole-induced cell-cycle arrest. Taken together, our results demonstrate that elastase is the first identified specific target protein for I3C and that the direct I3C inhibition of elastase enzymatic activity implicates the potential use of this indole, or related compounds, in targeted therapies of human breast cancers where high elastase levels are correlated with poor prognosis.A critical challenge in controlling breast cancer is the identification of therapeutic agents that can effectively control the growth of both estrogen-responsive and nonresponsive breast cancer cells with reduced side effects, especially during prolonged treatments. Epidemiological studies show that frequent consumption of certain vegetables is associated with a lower incidence of cancers at various sites (1). For example, the consumption of Brassica (cruciferous) vegetables, such as cabbage, broccoli, and Brussels sprouts, is directly associated with decreased risk of reproductive tissue cancers in humans (2, 3) and reduced tumor incidence in experimental animals (4). These studies implicate the existence of specific biologically active phytochemicals that represent a largely untapped source of potent chemotherapeutic agents. One such promising molecule is indole-3-carbinol (I3C), a natural compound derived from glycobrassicin in Brassica vegetables, which has been shown to exhibit potent anticarcinogenic properties in a wide range of cancers such as lung, liver, colon, cervical, endometrial, prostate, and breast cancer (5-7). In addition, out of broad spectrum of analyzed phytochemicals, I3C was 1 of the few that tested positive as a chemopreventative agent in a panel of short-term bioassays relevant to carcinogen-induced DNA damage, tumor initiat...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Nguyen¹,

Aronchik²,

Brar³

et al. 2008

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

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Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

Zhang

Deng

Liu

et al. 2020

Adv Funct Materials

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Breast cancer brain metastases (BCBMs) represent a major cause of morbidity and mortality among patients with breast cancer. Chemotherapy, which is widely used to treat tumors outside of the brain, is often ineffective on BCBMs due to its inability to efficiently cross the blood‐brain barrier (BBB). Although the BBB is partially disrupted in tumor lesions, it remains intact enough to prevent most therapeutics from entering the brain. Here, a nanotechnology approach is reported that can overcome the BBB through synthesis of lexiscan‐loaded, AMD3100‐conjugated, shrinkable nanoparticles (NPs), or LANPs. LANPs respond to neutrophil elastase–enriched tumor microenvironment by shrinking in size and disrupt the BBB in tumors through lexiscan‐mediated modulation. LANPs recognize tumor cells through the interaction between AMD3100 and CXCR4, which are expressed in metastatic tumor cells. The integration of tumor responsiveness, tumor targeting, and BBB penetration that enables LANPs to penetrate metastatic lesions in the brain with high efficiency is demonstrated and, when doxorubicin is encapsulated, LANPs effectively inhibit tumor growth and prolong the survival of tumor‐bearing mice. Due to their high efficiency in penetrating the BBB for BCBMs treatment, LANPs have the potential to be translated into clinical applications for improved treatment of patients with BCBMs.

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Beyond the horizon: Neutrophils leading the way in the evolution of immunotherapy

Rajgopal,

Nakano,

Cook

2023

Cancer Medicine

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Cancer is a complex and dynamic disease, initiated by a multitude of intrinsic mutations and progressed with the assistance of the tissue microenvironment, encompassed by stromal cells including immune cell infiltration. The novel finding that tumors can evade anti‐cancer immune functions shaped the field of immunotherapy, which has been a revolutionary approach for the treatment of cancers. However, the development of predominantly T cell‐targeted immunotherapy approaches, such as immune checkpoint inhibition, also brought about an accumulation of evidence demonstrating other immune cell drivers of tumor progression, such as innate immune cells and notably, neutrophils. In the past decade, neutrophils have emerged to be primary mediators of multiple cancer types and even in recent years, are gaining attention for their potential use in the next generation of immunotherapies. Here, we review current immunotherapy strategies and thoroughly discuss the roles of neutrophils in cancer and novel neutrophil‐targeted methods for treating cancer.

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Prognostic Significance of Immunoreactive Neutrophil Elastase in Human Breast Cancer: Long-Term Follow-Up Results in 313 Patients

Abstract: Tumor ir-NE concentration is an independent prognostic factor in patients with breast cancer who undergo curative surgery. This enzyme may play an active role in tumor progression that leads to metastasis in human breast cancer.

Cited by 57 publications

References 25 publications

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

The dietary phytochemical indole-3-carbinol is a natural elastase enzymatic inhibitor that disrupts cyclin E protein processing

Autocatalytic Delivery of Brain Tumor–Targeting, Size‐Shrinkable Nanoparticles for Treatment of Breast Cancer Brain Metastases

Beyond the horizon: Neutrophils leading the way in the evolution of immunotherapy

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