ORIGINAL ARTICLE

Overexpression of nuclear factor kappa B (NF-кB) protein as a risk factor for anthracyclin chemoresistance in luminal a subtype locally advanced breast cancer (LABC) at Sanglah General Hospital, Bali - Indonesia

Prabudi Prabudi, Ida Bagus Tjakra Wibawa Manuaba, I Wayan Sudarsa

Prabudi Prabudi
Surgical Oncology Trainee, Faculty of Medicine, Universitas Uayana-Sanglah General Hospital, Bali, Indonesia

Ida Bagus Tjakra Wibawa Manuaba
Surgical Oncology Subdivision, Department of Surgery, Faculty of Medicine, Universitas Uayana-Sanglah General Hospital, Bali, Indonesia

I Wayan Sudarsa
Surgical Oncology Subdivision, Department of Surgery, Faculty of Medicine, Universitas Uayana-Sanglah General Hospital, Bali, Indonesia. Email: [email protected]
Online First: October 23, 2020 | Cite this Article
Prabudi, P., Manuaba, I., Sudarsa, I. 2020. Overexpression of nuclear factor kappa B (NF-кB) protein as a risk factor for anthracyclin chemoresistance in luminal a subtype locally advanced breast cancer (LABC) at Sanglah General Hospital, Bali - Indonesia. Bali Medical Journal 9(3): 584-588. DOI:10.15562/bmj.v9i3.2041


Background: Around 68.6% of women who have breast cancer seek medical treatment at a locally advanced stage (LABC), where the neoadjuvant chemotherapy (NAC) modality is the initial choice therapy. Luminal A was recorded as the subtype with the chemotherapy response being the most resistant among others. The cause of chemoresistance is multi-factorial, and several studies correlate this condition with several anti-apoptotic agents expressed in the nucleus of cancer cells, especially nuclear factor-kappa B (NF-кB). The NF-κB transcription factor as an anti-apoptotic agent in some cancers blocks the apoptotic pathway through the extrinsic and intrinsic pathways. NF-κB plays a vital role in the development of chemoresistance. Understanding the NF-κB pathway and perceiving more about the cellular characteristics of LABC is very important to develop NF-κB inhibitors as therapy. NF-κB as a transcription factor can be considered a promising research target because it can affect oncogenes' transcription and play an essential role in prognostic and predictive biomarkers. This study was conducted to determine whether NF-κB overexpression is a risk factor for anthracycline-based neoadjuvant chemoresistance in Luminal A subtype LABC patients at Sanglah General Hospital.

Methods: An unpaired case-control study was conducted at Sanglah General Hospital. The research subjects were 40 people, divided into case groups (chemoresistance) and control groups (chemosensitive). Hereafter the NF-κB H-Score was carried out by IHC examination. Data are presented in table form and analyzed by Chi-square test or Fischer exact.

Results: Samples of cases with NF-κB overexpression were obtained 13 (65%), compared with the control group 7 (35%) (p<0.05). Multivariate analysis has shown that NF-κB overexpression is an independent factor against anthracycline-based chemotherapy resistance in advanced LABC patients with local luminal subtypes with p=0.013; OR 3.45 (95% CI=2.94-12.65).

Conclusion: NF-κB expression in Luminal A subtype LABC can be used as a predictor for anthracycline-based neoadjuvant chemoresistance. NF-κB overexpression is a predictor factor for NAC chemoresistance in luminal A subtype LABC.

References

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, dkk. Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. International Journal of Cancer. 2015;136:E359-86.

Kementerian Kesehatan RI. Riset Kementerian Kesehatan Dasar. Jakarta: Data dan Informasi Kesehatan; 2015.

Aggarwal BB, Takada Y, Shishodia S, Gutierrez AM, Oommen OV, Ichikawa H, dkk. Nuclear transcription factor NF- kappa B: Role in biology and medicine. Indian Journal of Experimental Biology. 2004;42:341-53.

Papademetriou K, Ardavanis A, Kountourakis P. Neoadjuvant therapy for locally advanced breast cancer: Focus on chemotherapy and biological targeted treatments’ armamentarium’. Journal of Thoracic Disease. 2010;2:160-70.

Montagut C. Activation of nuclear factor-B is linked to resistance to neoadjuvant chemotherapy in breast cancer patients. Endocrine Related Cancer. 2006;13:607-16.

Nielsen TO, Jensen MB, Burugu S, Gao D, Tykjaer Jørgensen CL, Balslev E, dkk. High-risk premenopausal Luminal A breast cancer patients derive no benefit from adjuvant cyclophosphamide-based chemotherapy: Results from the DBCG77B clinical trial. Clinical Cancer Research. 2017;23:946-53.

Godwin P, Baird AM, Heavey S, Barr MP, O'Byrne KJ, Gately K. Targeting Nuclear Factor-Kappa B to Overcome Resistance to Chemotherapy. Frontiers in Oncology. 2013;3:1-10.

Ho WC, Dickson KM, Barker PA. Nuclear Factor- κB Induced by Doxorubicin Is Deficient in Phosphorylation and Acetylation and Represses Nuclear Factor- κB − Dependent Transcription in Cancer Cells Phosphorylation and Acetylation and Represses Nuclear Factor- KB – Dependent Transcript. Cancer Research. 2005;65:4273-81.

Karin M, Lin A. NF-κB at the crossroads of life and death. Nature Immunology. 2002;3:221-7.

Gajdos C, Tartter PI, Estabrook A, Gistrak MA, Jaffer S, Bleiweiss IJ. Relationship of Clinical and Pathologic Response to Neoadjuvant Chemotherapy and Outcome of Locally Advanced Breast Cancer. Journal of Surgical Oncology. 2002;80:4-11.

Waldenfels GV, Loibl S, Furlanetto J, Machleidt A, Lederer B, Denkert C, dkk. Outcome after neoadjuvant chemotherapy in elderly breast cancer patients – a pooled analysis of individual patient data from eight prospectively randomized controlled trials. Oncotarget. 2018;9:15168-79.

Tubtimhin S, Promthet S, Suwanrungruang K, Supaattagorn P. Molecular Subtypes and Prognostic Factors among Premenopausal and Postmenopausal Thai Women with Invasive Breast Cancer : 15 Years Follow-up Data. Asian Pacific Journal of Cancer Prevention. 2018;19:3167-74.

Setyawati Y, Rahmawati Y, Widodo I, Ghozali A, Purnomosari D. The Association between Molecular Subtypes of Breast Cancer with Histological Grade and Lymph Node Metastases in Indonesian Woman. Asian Pacific Journal of Cancer Prevention. 2018;19:1263-8.

Blows FM, Driver KE, Schmidt MK, Broeks A, van Leeuwen FE, Wesseling J, dkk. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short- and long-term survival: A collaborative analysis of data for 10,159 cases from 12 studies. PLoS Medicine. PLoS Med. 2010;7:

He KW, Sun JJ, Liu ZB, Zhuo PY, Ma QH, Liu ZY, dkk. Prognostic significance of lymphatic vessel invasion diagnosed by D2-40 in Chinese invasive breast cancers. Medicine (Baltimore). 2017;96:e8490.

Sasanpour P, Sandoughdaran S, Mosavi JA, Malekzadeh M. Predictors of Pathological Complete Response to Neoadjuvant Chemotherapy in Iranian Breast Cancer Patients. Asian Pacific journal of Cancer Prevention. 2018;19:2423-7.

Kashiwagi S, Asano Y, Goto W, Morisaki T, Noda S, Takashima T, dkk. Prediction of the treatment response to neoadjuvant chemotherapy in breast cancer by subtypes using tumor-infiltrating lymphocytes. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR. Cancer Research. 2016;76(4 Suppl):Abstract nr P3-07-33.

Yang H, Wang W, Zhang Y, Zhao J, Lin E, Gao J, dkk. The role of NF-E2-related factor 2 in predicting chemoresistance and prognosis in advanced non-small-cell lung cancer. Clinical Lung Cancer. 2011;12:166-71.

Frasor J, Weaver A, Pradhan M, Dai Y, Miller LD, Lin CY, dkk. Positive cross-talk between estrogen receptor and NF- κB in breast cancer. Cancer Research. 2009;69:8918-25.

Sas L, Lardon F, Vermeulen PB, Hauspy J, Dam PV, Pauwels P, dkk. The interaction between ER and NFкB in resistance to endocrine therapy. Breast Cancer Research, 2012;14:1-14.

Rutering J, Ilmer M, Recio A, Coleman M, Vykoukal J, Alt E, dkk. NFκB Affects Estrogen Receptor Expression and Activity in Breast Cancer through Multiple Mechanisms. Nature Rev Drug Discovery. 2016;5:1-8.


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