Chronic Oxidative Stress Increases Growth and Tumorigenic Potential of MCF-7 Breast Cancer Cells

Abstract

Accumulating evidence suggests that exposures to elevated levels of either endogenous estrogen or environmental estrogenic chemicals are associated with breast cancer development and progression. These natural or synthetic estrogens are known to produce reactive oxygen species (ROS) and increased ROS has been implicated in both cellular apoptosis and carcinogenesis. Though there are several studies on direct involvement of ROS in cellular apoptosis using short-term exposure model, there is no experimental evidence to directly implicate chronic exposure to ROS in increased growth and tumorigenicity of breast cancer cells. Therefore, the objective of this study was to evaluate the effects of chronic oxidative stress on growth, survival and tumorigenic potential of MCF-7 breast cancer cells. MCF-7 cells were exposed to exogenous hydrogen peroxide (H2O2) as a source of ROS at doses of 25 µM and 250 µM for acute (24 hours) and chronic period (3 months) and their effects on cell growth/survival and tumorigenic potential were evaluated. The results of cell count, MTT and cell cycle analysis showed that while acute exposure inhibits the growth of MCF-7 cells in a dose-dependent manner, the chronic exposure to H2O2-induced ROS leads to increased cell growth and survival of MCF-7 cells. This was further confirmed by gene expression analysis of cell cycle and cell survival related genes. Significant increase in number of soft agar colonies, up-regulation of pro-metastatic genes VEGF, WNT1 and CD44, whereas down-regulation of anti-metastatic gene E-Cadherin in H2O2 treated MCF-7 cells observed in this study further suggests that persistent exposure to oxidative stress increases tumorigenic and metastatic potential of MCF-7 cells. Since many chemotherapeutic drugs are known to induce their cytotoxicity by increasing ROS levels, the results of this study are also highly significant in understanding the mechanism for adaptation to ROS-induced toxicity leading to acquired chemotherapeutic resistance in breast cancer cells.

Associations of persistent organic pollutants in serum and adipose tissue with breast cancer prognostic markers

“…In the present study, adipose tissue HCB concentrations were negatively associated with ECadherin expression. It has been reported that chronic exposure to POPs increases the production of reactive oxygen species (ROS), inducing the growth and survival of MCF-7 breast cancer cells and downregulating E-Cadherin expression (Mahalingaiah and Singh, 2014). In vivo and in vitro experimental studies found that PCB-mediated ROS production would induce invasiveness and metastasis by activating Rho-Associated Kinase (ROCK) activity (Liu et al, 2010).…”

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism

“…Persistent exposure to ROS (chronic oxidative stress) renders cancer cells physiologically adapted to ROS, thus facilitating increased survival (Mahalingaiah and Singh, 2014) through upregulation of Survivin, which abolishes the G2/M checkpoint and allows cells to progress through mitosis (Li et al, 1998). Owing to its antiapoptotic function, Survivin inhibits radiotherapy-and chemotherapy-induced cell death, thus resulting in tumor progression and drug resistance (Zaffaroni and Daidone, 2002;Schlette et al, 2004;Rödel et al, 2005;Fuessel et al, 2006).…”

“…Likewise, activation of nuclear factor kB has also been shown to be involved in chemotherapeutic resistance through various mechanisms, such as through upregulation of multidrug resistance (MDR) genes (Thévenod et al, 2000), increased expression of Bcl-2 (Viatour et al, 2003), and increased angiogenic vascular endothelial growth factor (Morais et al, 2009). Adaptation to chronic oxidative stress has been shown not only to increase the growth of cancer cells but also to affect directly the response to chemotherapy, as many anticancer drugs exert their cytotoxicity by generating ROS (Spitz et al, 1993;Scheltema et al, 2001;Mahalingaiah and Singh, 2014).…”

Checkpoint kinase 1 inhibitors as targeted molecular agents for clear cell carcinoma of the ovary

“…Several studies reported that continued oxidative stress leads not only to increased cell survival, but also increased tumorigenic potential of cancer cells (6,7). Oxidative stress contributes to the expansion of genomic instability throughout the genome, and subsequent gene mutations involved in the initiation of tumorigenesis (15).…”

“…Endometriosis also possesses a malignant transformation potential to ovarian carcinoma. Recently, several studies have indicated that heme and iron, present in endometriotic cysts, damage the endometriotic cells by inducing inflammation and oxidative stress (3)(4)(5)(6)(7). Simultaneously, several genes associated with acute antioxidant response, DNA damage repair and cell cycle modulation are activated.…”