Biochemical and Biophysical Research Communications
Advanced glycation end products promote triple negative breast cancer cells via ERK and NF-κB pathway
Introduction
Breast cancer is the most common cancer and the primary cause of cancer death in women around world [1]. Although advances in diagnostic and therapeutic modalities for last two decades improved the survival of breast cancer patients, triple-negative breast cancer (TNBC), which lacks the expression of estrogen receptors, progesterone receptors and human epidermal growth factor receptor-2, remains one of the most dangerous breast cancer subtypes [2,3]. TNBC has markedly high aggressive features among breast cancer subtypes with high recurrence rate, low overall survival during the first 3 years after diagnosis, and high frequency of metastases [[4], [5], [6], [7]]. Therefore, further understanding of the regulatory factors for TNBC progression is crucial for the development of therapeutic modalities for patients with TNBC.
Advanced glycation end products (AGEs) are harmful glycated proteins or lipids after exposure to sugars in the body or in processed foods [8]. AGEs were first discovered during the investigation of the non-enzymatic browning reaction by Maillard [9,10]. Today, AGEs are widely used in the food industry for improving taste [10,11]. In vivo, AGEs formation is slow because of relatively low reaction temperature. Accumulation of AGEs are accelerated by the high glucose levels in hyperglycemia and by aging [10,12,13]. AGEs stimulate cells via several receptors including advanced glycation end products (RAGE), oligosaccharyl transferase-48, scavenger receptors types I and II, galectin-3 and 80K-H phosphoprotein and trigger oxidative stress and inflammatory reactions [10]. Therefore, excessive accumulation of AGEs is involved in aging and diabetes-related disorders including retinopathy, cardiovascular diseases, Alzheimer's disease, nephropathy, neuropathy and cancers [[14], [15], [16], [17], [18], [19], [20]].
The effects of AGE accumulation on cancer progression have been studied. AGEs promote cell growth, migration, and invasion in the various cancer cell lines including melanoma, leukemia, colorectal cancer, hepatoblastoma and breast cancer cell lines [[21], [22], [23], [24], [25]]. In breast cancer, accumulation of the AGEs and increased expression of RAGE are positively associated with progression [26,27]. AGEs promote proliferation, migration and invasion of a breast cancer cell line, MDA-MB-231, with the enhanced expression of RAGE, activity of matrix metalloprotease (MMP)-9 and phosphorylation of extracellular-signal regulated kinase (ERK) [25]. However, the effect of AGEs on primary TNBC cells and the mechanism by which AGEs promote tumor progression in primary TNBC remains to be elucidated. In this study, we investigated the effects of AGEs on cell proliferation, tumorigenicity, migration and invasion of primary breast cancer cells and AGE-induced signaling pathways that mediate the effects of AGEs on primary breast cancer.
Section snippets
Derivation of human primary breast cancer cells
Human primary breast tumor tissues were obtained from breast cancer disease patients diagnosed as TNBC, determined by immunohistochemistry (Asan Medical Center, Seoul, Korea). Tumor tissues were minced and treated with collagenase type 3 for 18–20 h. After centrifugation, the cells were seeded onto collagen-coated plates. Primary breast cancer cells, in passages 2–6, were cultured in RPMI1640 medium (Hyclone, Logan, UT, USA) supplemented with 5% fetal bovine serum (FBS) (Hyclone), human
AGEs promote proliferation, tumorigenicity, invasion, and migration of primary breast cancer cells
To investigate the effects of AGEs on primary breast cancer cells, we initially measured the cell proliferation with different concentrations of AGEs. The number of viable cells increased for three days regardless of AGEs treatment. However, 80 μg/ml AGEs caused the number of viable cells to increase more rapidly than untreated control and lower concentration of AGE-treated breast cancer samples (Fig. 1A). Furthermore, treatment of 80 μg/ml AGEs or PMA (which was used as a positive control)
Discussion
Breast cancer is the leading cause of cancer death in women around world. Among subtypes, TNBC shows poor patient prognosis and low survival rate mainly due to the higher metastatic features than other subtypes [4,5]. Recently, development of new therapies and targets for the cure of TNBC has been attempted to overcome the limited efficacy of current therapies for TNBCs [2]. Therefore, elucidation of tumor microenvironmental or nutritional factors that effects the TNBC's progression is
Conflicts of interest
The authors have no conflict of interest to declare.
Acknowledgment
This research was supported by the grant (2016-0448) from the Asan Institute for Life Sciences (Seoul, Korea).
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