OSW‐1 inhibits tumor growth and metastasis by NFATc2 on triple‐negative breast cancer

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Abstract

OSW‐1 is a natural compound extracted from the bulbs of Ornithogalum saundersiae in 1992. It has been shown strong antitumor activities in various cancer cells. However, the effects of OSW‐1 on tumor growth and metastasis in breast cancer are still poorly understood. In our research, we showed that OSW‐1 had a strong anticancer effect on breast cancer cells, but lower toxicity to normal cells. Accordingly, it also revealed significant inhibition of tumor growth by OSW‐1 in xenograft model. In addition, we performed Annexin V/PI‐labeled flow cytometric assay and TUNEL assay and showed that OSW‐1 inhibited tumor growth by inducing apoptosis. Furthermore, we carried out transwell assays and found that OSW‐1 significantly repressed the migratory and invasive capabilities of triple‐negative breast cancer (TNBC) cells via mediating epithelial‐mesenchymal transition. Besides, OSW‐1 also could inhibit metastasis in an orthotopic model and resulted in a longer survival compared with control group. Finally, we performed RNA‐sequencing and cellular functions to investigate the molecular mechanism of how OSW‐1 inhibits TNBC, and identified NFATc2 may as a pivotal factor for OSW‐1‐mediated effects on cell death, tumor growth, invasion, and migration.

Abstract

OSW‐1, as a natural compound, could inhibit tumor growth by activating apoptosis and supress metastasis via epithelial‐mesenchymal transition in triple‐negative breast cancer (TNBC) both in vitro and in vivo. Besides, to investigate the molecular mechanism of how OSW‐1 inhibits TNBC, we performed RNA sequencing and cellular functions and considered that NFATc2 may act as a pivotal role in OSW‐1‐induced cell death, tumor growth, invasion, migration.

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Most cited references 24

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Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

, R Peto, C Davies … (2012)

Moderate differences in efficacy between adjuvant chemotherapy regimens for breast cancer are plausible, and could affect treatment choices. We sought any such differences. We undertook individual-patient-data meta-analyses of the randomised trials comparing: any taxane-plus-anthracycline-based regimen versus the same, or more, non-taxane chemotherapy (n=44,000); one anthracycline-based regimen versus another (n=7000) or versus cyclophosphamide, methotrexate, and fluorouracil (CMF; n=18,000); and polychemotherapy versus no chemotherapy (n=32,000). The scheduled dosages of these three drugs and of the anthracyclines doxorubicin (A) and epirubicin (E) were used to define standard CMF, standard 4AC, and CAF and CEF. Log-rank breast cancer mortality rate ratios (RRs) are reported. In trials adding four separate cycles of a taxane to a fixed anthracycline-based control regimen, extending treatment duration, breast cancer mortality was reduced (RR 0·86, SE 0·04, two-sided significance [2p]=0·0005). In trials with four such extra cycles of a taxane counterbalanced in controls by extra cycles of other cytotoxic drugs, roughly doubling non-taxane dosage, there was no significant difference (RR 0·94, SE 0·06, 2p=0·33). Trials with CMF-treated controls showed that standard 4AC and standard CMF were equivalent (RR 0·98, SE 0·05, 2p=0·67), but that anthracycline-based regimens with substantially higher cumulative dosage than standard 4AC (eg, CAF or CEF) were superior to standard CMF (RR 0·78, SE 0·06, 2p=0·0004). Trials versus no chemotherapy also suggested greater mortality reductions with CAF (RR 0·64, SE 0·09, 2p<0·0001) than with standard 4AC (RR 0·78, SE 0·09, 2p=0·01) or standard CMF (RR 0·76, SE 0·05, 2p<0·0001). In all meta-analyses involving taxane-based or anthracycline-based regimens, proportional risk reductions were little affected by age, nodal status, tumour diameter or differentiation (moderate or poor; few were well differentiated), oestrogen receptor status, or tamoxifen use. Hence, largely independently of age (up to at least 70 years) or the tumour characteristics currently available to us for the patients selected to be in these trials, some taxane-plus-anthracycline-based or higher-cumulative-dosage anthracycline-based regimens (not requiring stem cells) reduced breast cancer mortality by, on average, about one-third. 10-year overall mortality differences paralleled breast cancer mortality differences, despite taxane, anthracycline, and other toxicities. 10-year gains from a one-third breast cancer mortality reduction depend on absolute risks without chemotherapy (which, for oestrogen-receptor-positive disease, are the risks remaining with appropriate endocrine therapy). Low absolute risk implies low absolute benefit, but information was lacking about tumour gene expression markers or quantitative immunohistochemistry that might help to predict risk, chemosensitivity, or both. Cancer Research UK; British Heart Foundation; UK Medical Research Council. Copyright © 2012 Elsevier Ltd. All rights reserved.

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Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up.

L Malorni, P B Shetty, C. De Angelis … (2012)

Studies on well characterized, large populations of estrogen receptor (ER)/progesterone receptor (PgR)/HER2-negative [triple-negative (TN)] breast cancer (BC) patients with long-term follow-up are lacking. In this study, we analyze clinical outcomes of TN BC and implications of epidermal growth factor receptor (EGFR) expression. Clinical and biologic features, time to first recurrence (TTFR), and overall survival (OS) were compared in 253 TN versus 1,036 ER positive, PgR positive, HER2-negative [estrogen-driven (ED)] BC. Compared to ED, TN tumors were larger (p = 0.02), more proliferative (high S-phase 54 vs. 17 %, p < 0.0001), more aneuploid (64 vs. 43 %, p < 0.0001) and more likely EGFR positive (≥10 fmol/mg by radioligand-binding assay, 49 vs. 7 %, p < 0.0001). Among TN, EGFR-positive BC were larger (p = 0.0018), more proliferative (p < 0.0001), and more aneuploid, (p < 0.0001) than EGFR-negative BC. Adjuvant-treated TN patients had shorter TTFR (p = 0.0003), and OS (p = 0.0017), than ED patients. However, in untreated patients, no differences in TTFR and OS were observed at 8 years median follow-up. Among TN patients, EGFR expression was not associated with worse outcome. TN tumors have a worse outcome in systemically treated patients but not in untreated patients. EGFR expression, does not predict for worse long-term survival.

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Triple-negative breast cancer

Reinaldo D Chacón, María V Costanzo (2010)

Perou's molecular classification defines tumors that neither express hormone receptors nor overexpress HER2 as triple-negative (TN) tumors. These tumors account for approximately 15% of breast cancers. The so-called basaloid tumors are not always synonymous with TN tumors; they differ in the fact that they express different molecular markers, have a higher histologic grade, and have a worse prognosis. Clinically they occur in younger women as interval cancer, and the risk of recurrence is higher within the first 3 years. Distant recurrences in the brain and visceral metastases are more common than in hormone receptor-positive tumors. Therapeutically, despite being highly chemosensitive, their progression-free time is generally short. In terms of chemotherapeutic treatment, anthracyclines and taxanes are useful drugs, and high response rates have been described for the combination of ixabepilone-capecitabine and platinums. The combination with antiangiogenic drugs has also proven useful. A group of new drugs, poly-(ADP-ribose)-polymerase inhibitors, showed favorable results in TN tumors with BRCA mutation. There are currently several ongoing studies with new drugs including epidermal growth factor receptor inhibitors, c-kit inhibitors, Raf/Mek/Map kinase inhibitors and mTOR inhibitors.

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Author and article information

Contributors

Yongmei Yin:

ORCID: https://orcid.org/0000-0003-3335-369X

ymyin@njmu.edu.cn

Journal

Journal ID (nlm-ta): Cancer Med

Journal ID (iso-abbrev): Cancer Med

Journal ID (doi): 10.1002/(ISSN)2045-7634

Journal ID (publisher-id): CAM4

Title: Cancer Medicine

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2045-7634

Publication date (Electronic): 08 June 2020

Publication date Collection: August 2020

Volume: 9

Issue: 15 ( doiID: 10.1002/cam4.v9.15 )

Pages: 5558-5569

Affiliations

[ ¹ ] Department of Oncology The First Affiliated Hospital of Nanjing Medical University Nanjing China

[ ² ] Department of Oncology The Affiliated Huaian No.1 People’s Hospital of Nanjing Medical University Huaian China

Author notes

[*] [* ] Correspondence

Yongmei Yin, Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, No. 300 Guangzhou Rd, Nanjing 210029, China.

Email: ymyin@ 123456njmu.edu.cn

Author information

Xiaorong Ding https://orcid.org/0000-0002-7323-8146

Yongmei Yin https://orcid.org/0000-0003-3335-369X

Article

Publisher ID: CAM43196

DOI: 10.1002/cam4.3196

PMC ID: 7402832

PubMed ID: 32515123

SO-VID: 638af1d6-6fb6-4701-aa36-a9fed3a02b90

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

History

Date received : 27 January 2020

Date revision received : 21 April 2020

Date accepted : 11 May 2020

Page count

Figures: 7, Tables: 1, Pages: 12, Words: 5951

Funding

Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;

Award ID: 81702614

Award ID: 81972484

Funded by: Wu Jieping Medical Foundation , open-funder-registry 10.13039/100007452;

Award ID: 320.6750.17006

Funded by: Jiangsu Provincial Medical Youth Talent

Award ID: ZDRCA2016023

Funded by: 333 Project of Jiangsu Province

Award ID: BRA2015470

Award ID: BRA2017534

Funded by: National Key Research and Development Program of China

Award ID: 2017YFC0905901

Funded by: Project of Collaborative Innovation Center For Cancer Personalized Medicine of Nanjing Medical University

Award ID: JX21817902/008

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source-schema-version-number 2.0

cover-date August 2020

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.6 mode:remove_FC converted:04.08.2020

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: apoptosis,epithelial‐mesenchymal transition,metastasis,nfatc2,osw‐1,triple‐negative breast cancer

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: apoptosis, epithelial‐mesenchymal transition, metastasis, nfatc2, osw‐1, triple‐negative breast cancer

OSW‐1 inhibits tumor growth and metastasis by NFATc2 on triple‐negative breast cancer

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Most cited references 24

Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials.

Clinical and biologic features of triple-negative breast cancers in a large cohort of patients with long-term follow-up.

Triple-negative breast cancer

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