Research ArticleExperimental Studies
Open Access

The Contribution of Interleukin-8 Rs4073 Genotypes to Triple Negative Breast Cancer Risk in Taiwan

YUN-CHI WANG, ZHI-HONG WANG, JUNG-HSING YEN, YI-CHENG SHEN, TE-CHUN SHEN, WEN-SHIN CHANG, CHEN-HSIEN SU, KAI-YUAN CHEN, CHUN-MING YEN, HSU-TUNG LEE, JAI-SING YANG, DA-TIAN BAU and CHIA-WEN TSAI
Anticancer Research August 2022, 42 (8) 3799-3806; DOI: https://doi.org/10.21873/anticanres.15870

Abstract

Background/Aim: Triple negative breast cancer (TNBC) is one of the most challenging breast cancer types. Interleukin-8 (IL-8) is a pro-tumorigenic cytokine, promoting tumor proliferation and migration. This study aimed to examine the contribution of IL-8 rs4073 genotypes to breast cancer risk and provide a summary of related literature. Materials and Methods: IL-8 genotypic profiles were determined among 1,232 breast cancer cases and 1,232 controls via polymerase chain reaction-restriction fragment length polymorphism methodology. Results: The IL-8 rs4073 AT and AA genotypes had significantly lower prevalence in the case group compared to control group. Allelic frequency analysis showed that individuals carrying the A allele have relatively decreased risk for breast cancer. The stratification analysis showed that IL-8 rs4073 genotypes were protective markers for those with younger (≤55) age. Conclusion: IL-8 rs4073 A allele is a novel predictor for breast cancer, especially TNBC.

Key Words:

Breast cancer is the most prevalent and death-causing cancer among women worldwide (1). Although the survival rates of breast cancer patients have been improved with modern medical care, the breast cancer-related global death rate remains high (1). Among the several subtypes, triple negative breast cancer (TNBC) occupies 15%-20% of all invasive breast cancers and is characterized by a high metastasis and recurrence rate and poor survival (2, 3). Globally, TNBC is in lack of effective drugs. In Taiwan, breast cancer has the highest incidence among all cancers (4, 5). It is reported that high-caloric intake, high-fat diets, early menarche age, late menopause age, together with overweight/obesity, and exposure to pollutants are typical breast cancer risk factors in Taiwan (6). Several studies have investigated biomarkers and genetic variants for the early detection of breast cancer. For instance, carriers of BRCA1/BRCA2 mutations are at higher risk of breast cancer (7-10). However, BRCA1 and BRCA2 genetic variants can explain the etiology of a small percentage of breast cancer cases. Translational scientists are interested in identifying biomarkers for TNBC (11-13).

Chronic inflammation can induce DNA damage and may lead to carcinogenesis (14-16). Interleukin-8 (IL-8, also named CXCL8), is related to inflammation, and plays a role in many cellular processes including intersection of cancer plasticity, angiogenesis, and immune suppression (17). Normally, IL-8 is produced by many cell types such as monocytes, neutrophils, fibroblasts, macrophages, and endothelial cells (18, 19). Under certain abnormal conditions, IL-8 can also be produced by tumor cells, promoting the pro-tumorigenic processes of angiogenesis and cancer cell proliferation (20, 21). IL-8 has been shown to influence the processes of tumorigenesis of several types of cancer, such as melanoma, lung, colorectal, pancreatic, prostate and breast cancer (22). In literature, IL-8 has been reported to be over-expressed in some types of tumor cells, such as gastric, prostate, and breast cancer, and involved in invasion and metastasis (23-26). From a genomic viewpoint, several polymorphic sites in IL-8, T–251A, C+781T, C+1633T, and A+2767T, have associated with susceptibility to cancer (27). Among them, T–251A (rs4073) is the most commonly studied. The IL-8 rs4073, located in its promoter region, has been reported to be involved in the regulation of its protein levels. In detail, the A allele is responsible for a higher protein expression compared to the T allele (28, 29). Elevated IL-8 levels have been further reported to be associated with lung, colorectal, gastric, and breast cancer recurrence (30-33). Studies have shown that IL-8 genotypes are indeed associated with the risk for several types of cancer, including oral cancer (34, 35), nasopharyngeal cancer (27), lung cancer (36, 37), gastric cancer (38, 39), hepatoma (40), and prostate cancer (41). Regarding breast cancer, several studies have investigated the association of IL-8 rs4073 polymorphism and risk to breast cancer in Tunisia (42, 43), China (44), and Italy (45). However, conclusive evidence is still lacking.

Since the genetic background of Taiwanese is unique, geographically demarcated, and representative of East Asia, we aimed to examine the contribution of IL-8 rs4073 genotypes to breast cancer risk in Taiwan. In addition, we want to provide a summary of the literature to increase understanding of IL-8 genotype’s contribution to breast cancer risk.

Materials and Methods

Patients. Up to 1,232 female cases diagnosed with breast cancer in China Medical University Hospital in central Taiwan were recruited. The same number of healthy subjects was recruited from the Health Examination Cohort. The participants are all Taiwanese and the detailed procedure has been previously published (12, 46). Among all the breast cancer cases, 194 were identified as TNBC cases. Our study was approved and supervised by the Institutional Review Board (DMR-99-IRB-108). Specific demographic characteristics are summarized in Table I.

View this table:
Table I.

Demographics of the 1,232 breast cancer patients and 1,232 healthy controls.

Genotyping methodology for IL-8 rs4073. Peripheral blood was collected from all the study participants and genomic DNA was extracted within 24 h (47-49). The genotypes at IL-8 rs4073 were determined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) as previously published (36, 49, 50). Briefly, the forward and reverse primer sequences were 5’-TCATCCATGATCTTGTTCTA-3’ and 5’-GGAAAACGCTGTAG GTCAGA-3’, respectively. The PCR conditions were as follows: pre-denaturation at 94°C for 2 min; followed by 35 cycles of 94°C degeneration for 20 s, 57°C annealing for 20 s, 72°C extension for 20 s; and 72°C extension for 20 min. The adducts were cut with Mfe I. The digestible A-allele adducts were cut into two fragments of 449 + 75 bps, while T-allele adducts remained intact.

Statistical analysis. Typical Student’s t-test was used in evaluating the difference between the cases’ and controls’ age. Pearson’s chi-square test was used for evaluating the differential distribution of the IL-8 genotypes. The associations between the IL-8 genotypes and breast cancer risk were examined via calculating the odds ratios (ORs) and specific 95% confidence intervals (CIs) in stratification analysis. Results with p<0.05 were considered statistically significant.

Results

Demographic characteristics of the study population. The age, menarche age, age at birth of first child, menopause age, personal habits, tumor sites, TNBC status and family history of the recruited 1,232 breast cancer cases and the 1,232 healthy subjects are summarized and compared in Table I. There was no difference between the case and control groups in regards to age, age at menarche, age at first child birth, and age at menopause (all p>0.05) (Table I). There were more smokers and alcohol drinkers among the breast cancer patients than the controls (both p<0.0001) (Table I). Last, there were 194 TNBC cases and 97.2% of cases had unilateral breast cancer (Table I).

The genotypes of IL-8 rs4073 in the population. The genotypic distributions of IL-8 rs4073 among the controls and the breast cancer cases are shown in Tables II. The frequencies of IL-8 rs4073 genotypes among the controls fit the Hardy-Weinberg equilibrium (p=0.2306). The IL-8 rs4073 genotypes were differently distributed between the breast cancer and healthy control groups (p for trend=3.93*10–6). In detail, the IL-8 rs4073 hetero-variant AT and homo-variant AA genotypes were associated with a significantly decreased breast cancer risk, compared with the wild-type TT genotype (OR=0.67 and 0.64, 95%CI=0.56-0.80 and 0.51-0.81, p=0.0001 and 0.0002, respectively). Furthermore, AA genotype carriers had a significantly lower risk for breast cancer than those carrying TT+AT genotypes in the recessive model (OR=0.79, 95%CI=0.64-0.98, p=0.0344). AT+AA genotype carriers had a significantly lower risk for breast cancer than TT carriers in the dominant model (OR=0.66, 95%CI=0.56-0.78, p=0.0001). Variant AT and AA genotype carriers at IL-8 rs4073 have a decreased risk for breast cancer.

View this table:
Table II.

Interleukin-8 rs4073 genotypes among the 1,232 patients with breast cancer and 1,232 healthy controls.

The allelic frequencies of IL-8 rs4073 in the population. An allelic frequency distribution analysis for the IL-8 rs4073 was performed to validate the results deduced from Table II and Table III. Variant A allele frequency was lower (35.1%) in the breast cancer group than that (41.6%) in the control group (OR=0.76, 95%CI=0.68-0.85, p=0.0001, Table III).

View this table:
Table III.

Distribution of allelic frequencies for interleukin-8 rs4073 among 1,232 patients with breast cancer and 1,232 healthy controls.

IL-8 rs4073 genotype was associated with age. The genotyping results are stratified by age among the cases and controls (Table IV). Interestingly, the variant AT and TT genotypes at IL-8 rs4073 were associated with a decreased risk for breast cancer in those who are younger than or equal to 55 years old (OR=0.64 and 0.58, 95%CI=0.52-0.78 and 0.44-0.76, p=0.0001 and 0.0001, respectively). On the contrary, AT and TT genotypes at IL-8 rs4073 were not associated with altered risk for breast cancer for those who were older than 55 years old (OR=0.78 and 0.90, 95%CI=0.55-1.09 and 0.56-1.42, p=0.1667 and 0.7261, respectively).

View this table:
Table IV.

Interleukin-8 rs4073 genotype in breast cancer risk after stratification by age.

IL-8 rs4073 genotypes were associated with TNBC status. We examined whether IL-8 rs4073 genotype could be used as a biomarker for the prediction of TNBC risk. Thus, the breast cancer patients were further stratified into TNBC or non-TNBC patients. The results showed that among both the TNBC and non-TNBC cases, the protective effects of IL-8 rs4073 AT and AA genotypes were statistically significant (p=0.0015 and 0.0002 for TNBC and 0.0001 and 0.0048 for non-TNBC groups, respectively).

Discussion

Most cytokines are involved in carcinogenesis. Among them, IL-8 is a pro-tumorigenic mediator, promoting angiogenesis and cancer cell proliferation (20, 21, 51). Elevated levels of IL-8 have been reported to correspond to an increased breast cancer severity (52), as well as other types of cancer, including melanoma (53), pancreatic (54), gastric (55, 56), colorectal (57, 58), renal (59), prostate (60), and ovarian cancer (61). As for breast cancer, the induction of epithelial-to-mesenchymal transition (EMT) subsequently increased the activity of the IL-8/IL-8R cytokine signaling in cancer cells (1). In addition, IL-8 secreted from mesenchymal cells was able to induce EMT in surrounding epithelial cells, which was essential for the acquisition and maintenance of the metastatic phenotype of breast cancer cells (62). Furthermore, inhibition of IL-8 receptors resulted in a significant decrease in the invasive ability of breast cancer cells (62).

However, the contribution of IL-8 genotypes to breast cancer remains elusive, especially in Taiwan. In the present study, we examined the genotype profile of a representative population of 1,232 patients with breast cancer and 1,232 controls in Taiwan (Table I). Among breast cancer cases, the prevalence of IL-8 rs4073 AT and AA genotypes was significantly lower than that in controls (Table II). The results of allelic frequency analysis supported the idea that individuals carrying the A allele have decreased risk for breast cancer (Table III). The stratification analysis showed that IL-8 rs4073 genotypes were associated with younger (£55) age (Table IV). Furthermore, IL-8 rs4073 genotypes can serve as a biomarker for both TNBC and non-TNBC subtypes (Table V). Cigarette smoking and alcohol drinking contribute to breast cancer risk in Taiwan (Table I). However, the associations of IL-8 rs4073 genotypes with smoking and drinking were not specific (all p<0.05, data not shown).

View this table:
Table V.

Association of interleukin-8 rs4073 genotypes with breast cancer risk stratified with TNBC, non-TNBC, or healthy controls.

There are only a few studies examining the contribution of IL-8 rs4073 genotypes to breast cancer risk in the literature. We have summarized the contribution of IL-8 rs4073 genotypes to breast cancer risk (Table VI). As early as in 2004, Smith et al. firstly investigated the contribution of IL-8 rs4073 genotypes to breast cancer risk; however, no specific association of IL-8 rs4073 was found among a small English population containing 235 controls and 119 breast cancer cases (63). In 2006, Vogel et al. carried out a similar investigation in Denmark, however, no positive association was found (64). In the same year, Snoussi et al. found a positive association between IL-8 rs4073 AT and AA genotypes and higher breast cancer risk in a Tunisian population containing 308 breast cancer cases and 236 healthy controls (42). Four years later, the same group enlarged the investigated population to 409 breast cancer cases and 301 controls, and again found no association between IL-8 rs4073 AT and AA genotypes and higher breast cancer risk (43). In 2014, Wang et al. examined the genetic contribution of IL-8 rs4073 in 474 breast cancer cases and 501 controls in China. They found that TT genotypes of IL-8 rs4073 contributed to lower risk of breast cancer (44). In contrast, in 2017, Zhang et al. found that TT genotypes of IL-8 rs4073 contributed to a higher risk of breast cancer (65). The inconsistency cannot be explained since they investigated a similar population with the same methodology, and their control/case numbers were also the similar (442 cases and 447 controls). The samples of the current study are genetically and geographically conserved. Our findings are more consistent with those of Zhang et al.’s. To the best of our knowledge, we are the first to examine the association of IL-8 rs4073 with the risk of TNBC, finding that genotypes of IL-8 rs4073 can indeed serve as a predictor for the occurrence of TNBC. It is undeniable that there are differences among different ethnicities, and various types of breast cancer cases collected in different studies may also contribute to difference in the findings. All findings are valuable, but they need to be validated in larger sample size and various populations. Most of all, the researchers should keep good record about the subtypes of breast cancer samples.

View this table:
Table VI.

Summary of interleukin-8 rs4073 genotype in breast cancer risk.

In conclusion, the results of this study showed that IL-8 rs4073 genotypes, especially the A allele, may serve as an indicator for decreased risk of breast cancer. More importantly, it can server as a protective marker for TNBC. There are many ongoing clinical trials evaluating the addition of IL-8 targeting strategies to immune-based therapies, and the IL-8 rs4073 marker for breast cancer, especially TNBC, can add an extra value and importance to IL-8.

Acknowledgements

The Authors are grateful to the Tissue Bank of China Medical University Hospital and doctors/nurses for their excellent sample collection and technical assistance. The technical assistance from Yi-Ru Huang, Tzu-Yu Wang, Tzu-Hsuan Wang were very helpful in article preparation. This study was supported by China Medical University and Asia University, Taichung, Taiwan (CMU110-ASIA-03) and by Taichung Veterans General Hospital, Taichung, Taiwan (TCVGH-1115202B).

Footnotes

  • ↵* These Authors contributed equally to the study.

  • Authors’ Contributions

    Research design: Wang YC, Wang ZH and Yen JH; patient and questionnaire summaries: Lee HT, Shen YC and Shen TC; experimental work: Wang YC, Chang WS, CH SU and Yang JS; statistical analysis: Wang ZH, Chen KY and Yen CM; article writing: Wang YC and Tsai CW; review and revision: Tsai CW and Bau DT.

  • Conflicts of Interest

    The Authors declare no conflict of interest in relation to this study.

  • Received May 30, 2022.
  • Revision received June 20, 2022.
  • Accepted June 21, 2022.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

References

  1. ↵
    1. Siegel RL,
    2. Miller KD,
    3. Fuchs HE and
    4. Jemal A
    : Cancer statistics, 2022. CA Cancer J Clin 72(1): 7-33, 2022. PMID: 35020204. DOI: 10.3322/caac.21708
    OpenUrlCrossRefPubMed
  2. ↵
    1. Grigoriadis A,
    2. Mackay A,
    3. Noel E,
    4. Wu PJ,
    5. Natrajan R,
    6. Frankum J,
    7. Reis-Filho JS and
    8. Tutt A
    : Molecular characterisation of cell line models for triple-negative breast cancers. BMC Genomics 13: 619, 2012. PMID: 23151021. DOI: 10.1186/1471-2164-13-619
    OpenUrlCrossRefPubMed
  3. ↵
    1. Foulkes WD,
    2. Smith IE and
    3. Reis-Filho JS
    : Triple-negative breast cancer. N Engl J Med 363(20): 1938-1948, 2010. PMID: 21067385. DOI: 10.1056/NEJMra1001389
    OpenUrlCrossRefPubMed
  4. ↵
    1. Chien LH,
    2. Tseng TJ,
    3. Chen CH,
    4. Jiang HF,
    5. Tsai FY,
    6. Liu TW,
    7. Hsiung CA and
    8. Chang IS
    : Comparison of annual percentage change in breast cancer incidence rate between Taiwan and the United States-A smoothed Lexis diagram approach. Cancer Med 6(7): 1762-1775, 2017. PMID: 28560749. DOI: 10.1002/cam4.1102
    OpenUrlCrossRefPubMed
  5. ↵
    1. Taiwan Ministry of Health and Welfare Clinical Trial and Research Center of Excellence
    : Cancer Registration Annual Report. Available at: https://www.hpa.gov.tw/Pages/List.aspx?nodeid=269 [Last accessed on May 30, 2022]
  6. ↵
    1. Tsai HY,
    2. Kuo RN and
    3. Chung KP
    : Quality of life of breast cancer survivors following breast-conserving therapy versus mastectomy: a multicenter study in Taiwan. Jpn J Clin Oncol 47(10): 909-918, 2017. PMID: 28981734. DOI: 10.1093/jjco/hyx099
    OpenUrlCrossRefPubMed
  7. ↵
    1. Easton DF,
    2. Ford D and
    3. Bishop DT
    : Breast and ovarian cancer incidence in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet 56(1): 265-271, 1995. PMID: 7825587.
    OpenUrlCrossRefPubMed
    1. Struewing JP,
    2. Hartge P,
    3. Wacholder S,
    4. Baker SM,
    5. Berlin M,
    6. McAdams M,
    7. Timmerman MM,
    8. Brody LC and
    9. Tucker MA
    : The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336(20): 1401-1408, 1997. PMID: 9145676. DOI: 10.1056/NEJM199705153362001
    OpenUrlCrossRefPubMed
    1. Thorlacius S,
    2. Struewing JP,
    3. Hartge P,
    4. Olafsdottir GH,
    5. Sigvaldason H,
    6. Tryggvadottir L,
    7. Wacholder S,
    8. Tulinius H and
    9. Eyfjörd JE
    : Population-based study of risk of breast cancer in carriers of BRCA2 mutation. Lancet 352(9137): 1337-1339, 1998. PMID: 9802270. DOI: 10.1016/s0140-6736(98)03300-5
    OpenUrlCrossRefPubMed
  10. ↵
    1. Bau DT,
    2. Fu YP,
    3. Chen ST,
    4. Cheng TC,
    5. Yu JC,
    6. Wu PE and
    7. Shen CY
    : Breast cancer risk and the DNA double-strand break end-joining capacity of nonhomologous end-joining genes are affected by BRCA1. Cancer Res 64(14): 5013-5019, 2004. PMID: 15256476. DOI: 10.1158/0008-5472.CAN-04-0403
    OpenUrlAbstract/FREE Full Text
  11. ↵
    1. Bachmann HS,
    2. Jung D,
    3. Link T,
    4. Arnold A,
    5. Kantelhardt E,
    6. Thomssen C,
    7. Wimberger P,
    8. Vetter M and
    9. Kuhlmann JD
    : FNTB promoter polymorphisms are independent predictors of survival in patients with triple negative breast cancer. Cancers (Basel) 14(3): 468, 2022. PMID: 35158735. DOI: 10.3390/cancers14030468
    OpenUrlCrossRefPubMed
  12. ↵
    1. Chen KY,
    2. Chien WC,
    3. Liao JM,
    4. Tsai CW,
    5. Chang WS,
    6. Su CH,
    7. Hsu SW,
    8. Wang HC and
    9. Bau DT
    : Contribution of Interleukin-10 genotype to triple negative breast cancer risk. Anticancer Res 41(5): 2451-2457, 2021. PMID: 33952470. DOI: 10.21873/anticanres.15020
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Al Hamad M,
    2. Kussaibi H,
    3. Alkharsah KR,
    4. Alsayyah A,
    5. El Shawarby M,
    6. Al Tamimi D,
    7. Alomari M,
    8. Bakshi HA,
    9. Tambuwala MM and
    10. Al Zoubi MS
    : Polymorphic variants in 5’-UTR regions of the RAD51 gene are associated with RAD51 expression and triple-negative breast cancer (TNBC): a case-control study. Appl Immunohistochem Mol Morphol 29(4): 270-276, 2021. PMID: 33417321. DOI: 10.1097/PAI.0000000000000900
    OpenUrlCrossRefPubMed
  14. ↵
    1. Hussain SP,
    2. Hofseth LJ and
    3. Harris CC
    : Radical causes of cancer. Nat Rev Cancer 3(4): 276-285, 2003. PMID: 12671666. DOI: 10.1038/nrc1046
    OpenUrlCrossRefPubMed
    1. Balkwill F
    : The significance of cancer cell expression of the chemokine receptor CXCR4. Semin Cancer Biol 14(3): 171-179, 2004. PMID: 15246052. DOI: 10.1016/j.semcancer.2003.10.003
    OpenUrlCrossRefPubMed
  16. ↵
    1. Zlotnik A
    : Chemokines in neoplastic progression. Semin Cancer Biol 14(3): 181-185, 2004. PMID: 15246053. DOI: 10.1016/j.semcancer.2003.10.004
    OpenUrlCrossRefPubMed
  17. ↵
    1. Fousek K,
    2. Horn LA and
    3. Palena C
    : Interleukin-8: A chemokine at the intersection of cancer plasticity, angiogenesis, and immune suppression. Pharmacol Ther 219: 107692, 2021. PMID: 32980444. DOI: 10.1016/j.pharmthera.2020.107692
    OpenUrlCrossRefPubMed
  18. ↵
    1. Rollins BJ
    : Chemokines. Blood 90(3): 909-928, 1997. PMID: 9242519.
    OpenUrlFREE Full Text
  19. ↵
    1. Waugh DJ and
    2. Wilson C
    : The interleukin-8 pathway in cancer. Clin Cancer Res 14(21): 6735-6741, 2008. PMID: 18980965. DOI: 10.1158/1078-0432.CCR-07-4843
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. van Aken BE,
    2. Reitsma PH and
    3. Rosendaal FR
    : Interleukin 8 and venous thrombosis: evidence for a role of inflammation in thrombosis. Br J Haematol 116(1): 173-177, 2002. PMID: 11841414. DOI: 10.1046/j.1365-2141.2002.03245.x
    OpenUrlCrossRefPubMed
  21. ↵
    1. Koch AE,
    2. Polverini PJ,
    3. Kunkel SL,
    4. Harlow LA,
    5. DiPietro LA,
    6. Elner VM,
    7. Elner SG and
    8. Strieter RM
    : Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science 258(5089): 1798-1801, 1992. PMID: 1281554. DOI: 10.1126/science.1281554
    OpenUrlAbstract/FREE Full Text
  22. ↵
    1. Cheng Y,
    2. Ma XL,
    3. Wei YQ and
    4. Wei XW
    : Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochim Biophys Acta Rev Cancer 1871(2): 289-312, 2019. PMID: 30703432. DOI: 10.1016/j.bbcan.2019.01.005
    OpenUrlCrossRefPubMed
  23. ↵
    1. Kitadai Y,
    2. Haruma K,
    3. Mukaida N,
    4. Ohmoto Y,
    5. Matsutani N,
    6. Yasui W,
    7. Yamamoto S,
    8. Sumii K,
    9. Kajiyama G,
    10. Fidler IJ and
    11. Tahara E
    : Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8. Clin Cancer Res 6(7): 2735-2740, 2000. PMID: 10914718.
    OpenUrlAbstract/FREE Full Text
    1. Bendre MS,
    2. Gaddy-Kurten D,
    3. Mon-Foote T,
    4. Akel NS,
    5. Skinner RA,
    6. Nicholas RW and
    7. Suva LJ
    : Expression of interleukin 8 and not parathyroid hormone-related protein by human breast cancer cells correlates with bone metastasis in vivo. Cancer Res 62(19): 5571-5579, 2002. PMID: 12359770.
    OpenUrlAbstract/FREE Full Text
    1. Li A,
    2. Dubey S,
    3. Varney ML,
    4. Dave BJ and
    5. Singh RK
    : IL-8 directly enhanced endothelial cell survival, proliferation, and matrix metalloproteinases production and regulated angiogenesis. J Immunol 170(6): 3369-3376, 2003. PMID: 12626597. DOI: 10.4049/jimmunol.170.6.3369
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Matsui T,
    2. Ojima A,
    3. Higashimoto Y,
    4. Taira J,
    5. Fukami K and
    6. Yamagishi SI
    : Pigment epithelium-derived factor inhibits caveolin-induced interleukin-8 gene expression and proliferation of human prostate cancer cells. Oncol Lett 10(4): 2644-2648, 2015. PMID: 26622904. DOI: 10.3892/ol.2015.3568
    OpenUrlCrossRefPubMed
  27. ↵
    1. Huang CY,
    2. Chang WS,
    3. Tsai CW,
    4. Hsia TC,
    5. Shen TC,
    6. Bau DT and
    7. Shui HA
    : The contribution of interleukin-8 genotypes and expression to nasopharyngeal cancer susceptibility in Taiwan. Medicine (Baltimore) 97(36): e12135, 2018. PMID: 30200105. DOI: 10.1097/MD.0000000000012135
    OpenUrlCrossRefPubMed
  28. ↵
    1. Hull J,
    2. Thomson A and
    3. Kwiatkowski D
    : Association of respiratory syncytial virus bronchiolitis with the interleukin 8 gene region in UK families. Thorax 55(12): 1023-1027, 2000. PMID: 11083887. DOI: 10.1136/thorax.55.12.1023
    OpenUrlAbstract/FREE Full Text
  29. ↵
    1. Araki S,
    2. Omori Y,
    3. Lyn D,
    4. Singh RK,
    5. Meinbach DM,
    6. Sandman Y,
    7. Lokeshwar VB and
    8. Lokeshwar BL
    : Interleukin-8 is a molecular determinant of androgen independence and progression in prostate cancer. Cancer Res 67(14): 6854-6862, 2007. PMID: 17638896. DOI: 10.1158/0008-5472.CAN-07-1162
    OpenUrlAbstract/FREE Full Text
  30. ↵
    1. Taguchi A,
    2. Ohmiya N,
    3. Shirai K,
    4. Mabuchi N,
    5. Itoh A,
    6. Hirooka Y,
    7. Niwa Y and
    8. Goto H
    : Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev 14(11 Pt 1): 2487-2493, 2005. PMID: 16284368. DOI: 10.1158/1055-9965.EPI-05-0326
    OpenUrlAbstract/FREE Full Text
    1. Ahmed OI,
    2. Adel AM,
    3. Diab DR and
    4. Gobran NS
    : Prognostic value of serum level of interleukin-6 and interleukin-8 in metastatic breast cancer patients. Egypt J Immunol 13(2): 61-68, 2006. PMID: 18689272.
    OpenUrlPubMed
    1. Lurje G,
    2. Zhang W,
    3. Schultheis AM,
    4. Yang D,
    5. Groshen S,
    6. Hendifar AE,
    7. Husain H,
    8. Gordon MA,
    9. Nagashima F,
    10. Chang HM and
    11. Lenz HJ
    : Polymorphisms in VEGF and IL-8 predict tumor recurrence in stage III colon cancer. Ann Oncol 19(10): 1734-1741, 2008. PMID: 18550579. DOI: 10.1093/annonc/mdn368
    OpenUrlCrossRefPubMed
  33. ↵
    1. Millar HJ,
    2. Nemeth JA,
    3. McCabe FL,
    4. Pikounis B and
    5. Wickstrom E
    : Circulating human interleukin-8 as an indicator of cancer progression in a nude rat orthotopic human non-small cell lung carcinoma model. Cancer Epidemiol Biomarkers Prev 17(8): 2180-2187, 2008. PMID: 18708412. DOI: 10.1158/1055-9965.EPI-07-2915
    OpenUrlAbstract/FREE Full Text
  34. ↵
    1. Singh PK,
    2. Chandra G,
    3. Bogra J,
    4. Gupta R,
    5. Kumar V,
    6. Hussain SR,
    7. Jain A,
    8. Mahdi AA and
    9. Ahmad MK
    : Association of genetic polymorphism in the Interleukin-8 gene with risk of oral cancer and its correlation with pain. Biochem Genet 54(1): 95-106, 2016. PMID: 26660080. DOI: 10.1007/s10528-015-9704-y
    OpenUrlCrossRefPubMed
  35. ↵
    1. Shimizu Y,
    2. Kondo S,
    3. Shirai A,
    4. Furukawa M and
    5. Yoshizaki T
    : A single nucleotide polymorphism in the matrix metalloproteinase-1 and interleukin-8 gene promoter predicts poor prognosis in tongue cancer. Auris Nasus Larynx 35(3): 381-389, 2008. PMID: 18276095. DOI: 10.1016/j.anl.2007.12.002
    OpenUrlCrossRefPubMed
  36. ↵
    1. Li CH,
    2. Yang YC,
    3. Hsia TC,
    4. Shen TC,
    5. Shen YC,
    6. Chang WS,
    7. Wang YC,
    8. Tsai CW and
    9. Bau DT
    : Association of Interleukin-8 promoter genotypes with Taiwan lung cancer risk. Anticancer Res 42(3): 1229-1236, 2022. PMID: 35220213. DOI: 10.21873/anticanres.15590
    OpenUrlAbstract/FREE Full Text
  37. ↵
    1. Kaanane H,
    2. Senhaji N,
    3. Berradi H,
    4. Benchakroun N,
    5. Benider A,
    6. Karkouri M,
    7. El Attar H,
    8. Flores O,
    9. Khyatti M and
    10. Nadifi S
    : The influence of Interleukin-6, Interleukin-8, Interleukin-10, Interleukin-17, TNF-A, MIF, STAT3 on lung cancer risk in Moroccan population. Cytokine 151: 155806, 2022. PMID: 35065510. DOI: 10.1016/j.cyto.2022.155806
    OpenUrlCrossRefPubMed
  38. ↵
    1. Chang YW,
    2. Oh CH,
    3. Kim JW,
    4. Lee JW,
    5. Park MJ,
    6. Shim JJ,
    7. Lee CK,
    8. Jang JY,
    9. Dong SH,
    10. Kim HJ,
    11. Kim SS and
    12. Kim BH
    : Combination of Helicobacter pylori infection and the interleukin 8 -251 T > A polymorphism, but not the mannose-binding lectin 2 codon 54 G > A polymorphism, might be a risk factor of gastric cancer. BMC Cancer 17(1): 388, 2017. PMID: 28558668. DOI: 10.1186/s12885-017-3378-2
    OpenUrlCrossRefPubMed
  39. ↵
    1. Cheng D,
    2. Hao Y,
    3. Zhou W and
    4. Ma Y
    : Positive association between Interleukin-8 -251A > T polymorphism and susceptibility to gastric carcinogenesis: a meta-analysis. Cancer Cell Int 13(1): 100, 2013. PMID: 24143859. DOI: 10.1186/1475-2867-13-100
    OpenUrlCrossRefPubMed
  40. ↵
    1. Chien MH,
    2. Yeh CB,
    3. Li YC,
    4. Wei LH,
    5. Chang JH,
    6. Peng YT,
    7. Yang SF and
    8. Kuo WH
    : Relationship of interleukin-8 gene polymorphisms with hepatocellular carcinoma susceptibility and pathological development. J Surg Oncol 104(7): 798-803, 2011. PMID: 21780129. DOI: 10.1002/jso.22037
    OpenUrlCrossRefPubMed
  41. ↵
    1. Chen CH,
    2. Ho CH,
    3. Hu SW,
    4. Tzou KY,
    5. Wang YH and
    6. Wu CC
    : Association between interleukin-8 rs4073 polymorphism and prostate cancer: A meta-analysis. J Formos Med Assoc 119(7): 1201-1210, 2020. PMID: 31718853. DOI: 10.1016/j.jfma.2019.10.016
    OpenUrlCrossRefPubMed
  42. ↵
    1. Snoussi K,
    2. Mahfoudh W,
    3. Bouaouina N,
    4. Ahmed SB,
    5. Helal AN and
    6. Chouchane L
    : Genetic variation in IL-8 associated with increased risk and poor prognosis of breast carcinoma. Hum Immunol 67(1-2): 13-21, 2006. PMID: 16698420. DOI: 10.1016/j.humimm.2006.03.018
    OpenUrlCrossRefPubMed
  43. ↵
    1. Snoussi K,
    2. Mahfoudh W,
    3. Bouaouina N,
    4. Fekih M,
    5. Khairi H,
    6. Helal AN and
    7. Chouchane L
    : Combined effects of IL-8 and CXCR2 gene polymorphisms on breast cancer susceptibility and aggressiveness. BMC Cancer 10: 283, 2010. PMID: 20540789. DOI: 10.1186/1471-2407-10-283
    OpenUrlCrossRefPubMed
  44. ↵
    1. Wang Z,
    2. Liu QL,
    3. Sun W,
    4. Yang CJ,
    5. Tang L,
    6. Zhang X and
    7. Zhong XM
    : Genetic polymorphisms in inflammatory response genes and their associations with breast cancer risk. Croat Med J 55(6): 638-646, 2014. PMID: 25559835. DOI: 10.3325/cmj.2014.55.638
    OpenUrlCrossRefPubMed
  45. ↵
    1. Di Salvatore M,
    2. Lo Giudice L,
    3. Rossi E,
    4. Santonocito C,
    5. Nazzicone G,
    6. Rodriquenz MG,
    7. Cappuccio S,
    8. Inno A,
    9. Fuso P,
    10. Orlandi A,
    11. Strippoli A,
    12. Capoluongo E,
    13. Astone A,
    14. Cassano A and
    15. Barone C
    : Association of IL-8 and eNOS polymorphisms with clinical outcomes in bevacizumab-treated breast cancer patients: an exploratory analysis. Clin Transl Oncol 18(1): 40-46, 2016. PMID: 26141413. DOI: 10.1007/s12094-015-1334-7
    OpenUrlCrossRefPubMed
  46. ↵
    1. Wang YC,
    2. Wang ZH,
    3. Shen TC,
    4. Chang WS,
    5. Huang SZ,
    6. Yu CC,
    7. Chen JC,
    8. Hsiau YC,
    9. Yang JS,
    10. Tsai CW and
    11. Bau DT
    : Contribution of Interleukin-12A genotypes to breast cancer risk. Anticancer Res 41(9): 4387-4393, 2021. PMID: 34475058. DOI: 10.21873/anticanres.15243
    OpenUrlAbstract/FREE Full Text
  47. ↵
    1. Wu MH,
    2. Chen CH,
    3. Chen CP,
    4. Huang TL,
    5. Yueh TC,
    6. Wang ZH,
    7. Tsai CW,
    8. Pei JS,
    9. Mong MC,
    10. Yang YC,
    11. Bau DT and
    12. Chang WS
    : Contribution of 5-Methyltetrahydrofolate-Homocysteine Methyltransferase Reductase genotypes to colorectal cancer in Taiwan. Anticancer Res 42(5): 2375-2382, 2022. PMID: 35489763. DOI: 10.21873/anticanres.15716
    OpenUrlAbstract/FREE Full Text
    1. Fu CK,
    2. Mong MC,
    3. Yu CC,
    4. Yang MD,
    5. Wang ZH,
    6. Yang YC,
    7. Chen JC,
    8. Pei JS,
    9. Hsia NY,
    10. Tsai CW,
    11. Chang WS and
    12. Bau DT
    : Association of Matrix Metallopeptidase-2 genotypes with risk of gastric cancer in Taiwan. Anticancer Res 42(4): 1749-1755, 2022. PMID: 35346993. DOI: 10.21873/anticanres.15651
    OpenUrlAbstract/FREE Full Text
  49. ↵
    1. Pei JS,
    2. Chang WS,
    3. Chen CC,
    4. Mong MC,
    5. Hsu SW,
    6. Hsu PC,
    7. Hsu YN,
    8. Wang YC,
    9. Tsai CW and
    10. Bau DT
    : Novel contribution of long non-coding RNA MEG3 genotype to prediction of childhood leukemia risk. Cancer Genomics Proteomics 19(1): 27-34, 2022. PMID: 34949657. DOI: 10.21873/cgp.20301
    OpenUrlAbstract/FREE Full Text
  50. ↵
    1. Yang MD,
    2. Lin KC,
    3. Lu MC,
    4. Jeng LB,
    5. Hsiao CL,
    6. Yueh TC,
    7. Fu CK,
    8. Li HT,
    9. Yen ST,
    10. Lin CW,
    11. Wu CW,
    12. Pang SY,
    13. Bau DT and
    14. Tsai FJ
    : Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan. Biomedicine (Taipei) 7(2): 10, 2017. PMID: 28612708. DOI: 10.1051/bmdcn/2017070203
    OpenUrlCrossRefPubMed
  51. ↵
    1. Rizzo A,
    2. Losacco A and
    3. Carratelli CR
    : Lactobacillus crispatus modulates epithelial cell defense against Candida albicans through Toll-like receptors 2 and 4, interleukin 8 and human β-defensins 2 and 3. Immunol Lett 156(1-2): 102-109, 2013. PMID: 24120511. DOI: 10.1016/j.imlet.2013.08.013
    OpenUrlCrossRefPubMed
  52. ↵
    1. Miller LJ,
    2. Kurtzman SH,
    3. Wang Y,
    4. Anderson KH,
    5. Lindquist RR and
    6. Kreutzer DL
    : Expression of interleukin-8 receptors on tumor cells and vascular endothelial cells in human breast cancer tissue. Anticancer Res 18(1A): 77-81, 1998. PMID: 9568059.
    OpenUrlPubMed
  53. ↵
    1. Huang S,
    2. Mills L,
    3. Mian B,
    4. Tellez C,
    5. McCarty M,
    6. Yang XD,
    7. Gudas JM and
    8. Bar-Eli M
    : Fully humanized neutralizing antibodies to interleukin-8 (ABX-IL8) inhibit angiogenesis, tumor growth, and metastasis of human melanoma. Am J Pathol 161(1): 125-134, 2002. PMID: 12107097. DOI: 10.1016/S0002-9440(10)64164-8
    OpenUrlCrossRefPubMed
  54. ↵
    1. Shi Q,
    2. Abbruzzese JL,
    3. Huang S,
    4. Fidler IJ,
    5. Xiong Q and
    6. Xie K
    : Constitutive and inducible interleukin 8 expression by hypoxia and acidosis renders human pancreatic cancer cells more tumorigenic and metastatic. Clin Cancer Res 5(11): 3711-3721, 1999. PMID: 10589791.
    OpenUrlAbstract/FREE Full Text
  55. ↵
    1. Zhang XY,
    2. Chan WY,
    3. Whitney BM,
    4. Fan DM,
    5. Chow JH,
    6. Liu Y,
    7. Ng EK and
    8. Chung SC
    : Changes of interleukin expression correlate with Helicobacter pylori infection and lymph node metastases in gastric carcinoma. Diagn Mol Pathol 11(3): 135-139, 2002. PMID: 12218451. DOI: 10.1097/00019606-200209000-00002
    OpenUrlCrossRefPubMed
  56. ↵
    1. Lee KH,
    2. Bae SH,
    3. Lee JL,
    4. Hyun MS,
    5. Kim SH,
    6. Song SK and
    7. Kim HS
    : Relationship between urokinase-type plasminogen receptor, interleukin-8 gene expression and clinicopathological features in gastric cancer. Oncology 66(3): 210-217, 2004. PMID: 15218312. DOI: 10.1159/000077997
    OpenUrlCrossRefPubMed
  57. ↵
    1. Li A,
    2. Varney ML and
    3. Singh RK
    : Expression of interleukin 8 and its receptors in human colon carcinoma cells with different metastatic potentials. Clin Cancer Res 7(10): 3298-3304, 2001. PMID: 11595728.
    OpenUrlAbstract/FREE Full Text
  58. ↵
    1. Chung YC and
    2. Chang YF
    : Significance of inflammatory cytokines in the progression of colorectal cancer. Hepatogastroenterology 50(54): 1910-1913, 2003. PMID: 14696431.
    OpenUrlPubMed
  59. ↵
    1. Slaton JW,
    2. Inoue K,
    3. Perrotte P,
    4. El-Naggar AK,
    5. Swanson DA,
    6. Fidler IJ and
    7. Dinney CP
    : Expression levels of genes that regulate metastasis and angiogenesis correlate with advanced pathological stage of renal cell carcinoma. Am J Pathol 158(2): 735-743, 2001. PMID: 11159211. DOI: 10.1016/S0002-9440(10)64016-3
    OpenUrlCrossRefPubMed
  60. ↵
    1. Uehara H,
    2. Troncoso P,
    3. Johnston D,
    4. Bucana CD,
    5. Dinney C,
    6. Dong Z,
    7. Fidler IJ and
    8. Pettaway CA
    : Expression of interleukin-8 gene in radical prostatectomy specimens is associated with advanced pathologic stage. Prostate 64(1): 40-49, 2005. PMID: 15651067. DOI: 10.1002/pros.20223
    OpenUrlCrossRefPubMed
  61. ↵
    1. Venkatakrishnan G,
    2. Salgia R and
    3. Groopman JE
    : Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase via the epidermal growth factor receptor in ovarian cancer cells. J Biol Chem 275(10): 6868-6875, 2000. PMID: 10702246. DOI: 10.1074/jbc.275.10.6868
    OpenUrlAbstract/FREE Full Text
  62. ↵
    1. Fernando RI,
    2. Castillo MD,
    3. Litzinger M,
    4. Hamilton DH and
    5. Palena C
    : IL-8 signaling plays a critical role in the epithelial-mesenchymal transition of human carcinoma cells. Cancer Res 71(15): 5296-5306, 2011. PMID: 21653678. DOI: 10.1158/0008-5472.CAN-11-0156
    OpenUrlAbstract/FREE Full Text
  63. ↵
    1. Smith KC,
    2. Bateman AC,
    3. Fussell HM and
    4. Howell WM
    : Cytokine gene polymorphisms and breast cancer susceptibility and prognosis. Eur J Immunogenet 31(4): 167-173, 2004. PMID: 15265021. DOI: 10.1111/j.1365-2370.2004.00462.x
    OpenUrlCrossRefPubMed
  64. ↵
    1. Vogel U,
    2. Christensen J,
    3. Nexø BA,
    4. Wallin H,
    5. Friis S and
    6. Tjønneland A
    : Peroxisome proliferator-activated [corrected] receptor-gamma2 [corrected] Pro12Ala, interaction with alcohol intake and NSAID use, in relation to risk of breast cancer in a prospective study of Danes. Carcinogenesis 28(2): 427-434, 2007. PMID: 16959787. DOI: 10.1093/carcin/bgl170
    OpenUrlCrossRefPubMed
  65. ↵
    1. Zhang J,
    2. Han X and
    3. Sun S
    : IL-8 -251A/T and +781C/T polymorphisms were associated with risk of breast cancer in a Chinese population. Int J Clin Exp Pathol 10(7): 7443-7450, 2017. PMID: 31966587.
    OpenUrlPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
The Contribution of Interleukin-8 Rs4073 Genotypes to Triple Negative Breast Cancer Risk in Taiwan
YUN-CHI WANG, ZHI-HONG WANG, JUNG-HSING YEN, YI-CHENG SHEN, TE-CHUN SHEN, WEN-SHIN CHANG, CHEN-HSIEN SU, KAI-YUAN CHEN, CHUN-MING YEN, HSU-TUNG LEE, JAI-SING YANG, DA-TIAN BAU, CHIA-WEN TSAI
Anticancer Research Aug 2022, 42 (8) 3799-3806; DOI: 10.21873/anticanres.15870
Reddit logo Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords