Cellular and molecular mechanisms underlying alcohol-induced aggressiveness of breast cancer

Abstract

Breast cancer is a leading cause of morbidity and mortality in women. Both Epidemiological and experimental studies indicate a positive correlation between alcohol consumption and the risk of breast cancer. While alcohol exposure may promote the carcinogenesis or onset of breast cancer, it may as well enhance the progression and aggressiveness of existing mammary tumors. Recent progress in this line of research suggests that alcohol exposure is associated with invasive breast cancer and promotes the growth and metastasis of mammary tumors. There are multiple potential mechanisms involved in alcohol-stimulated progression and aggressiveness of breast cancer. Alcohol may increase the mobility of cancer cells by inducing cytoskeleton reorganization and enhancing the cancer cell invasion by causing degradation and reconstruction of the extracellular matrix (ECM). Moreover, alcohol may promote the epithelial-mesenchymal transition (EMT), a hallmark of malignancy, and impair endothelial integrity, thereby increasing the dissemination of breast cancer cells and facilitating metastasis. Furthermore, alcohol may stimulate tumor angiogenesis through the activation of cytokines and chemokines which promotes tumor growth. Additionally, alcohol may increase the cancer stem cell population which affects neoplastic cell behavior, aggressiveness, and the therapeutic response. Alcohol can be metabolized in the mammary tissues and breast cancer cells which produces reactive oxygen species (ROS), causing oxidative stress. Recent studies suggest that the epidermal growth factor receptor (EGFR) family, particularly ErbB2 (a member of this family), is involved in alcohol-mediated tumor promotion. Breast cancer cells or mammary epithelial cells over-expressing ErbB2 are more sensitive to alcohol's tumor promoting effects. There is considerable cross-talk between oxidative stress and EGFR/ErbB2 signaling. This review further discusses how the interaction between oxidative stress and EGFR/ErbB2 signaling contributes to the cellular and molecular events associated with breast cancer aggressiveness. We also discuss the potential therapeutic approaches for cancer patients who drink alcoholic beverages.

Keywords: Alcoholism; Cancer stem cells; Carcinogenesis; Estrogen; HER2/ErbB2; Oxidative stress.

Figure 1

Alcohol promotes cancer metastasis and the activation of ErbB2. A: FVB MMTV Neu mice were fed with liquid diet containing ethanol (0 or 6.7%). After tumors reached a maximal diameter of 20 mm, mice were sacrificed and analyzed for tumor metastasis. Alcohol consumption significantly increased the metastases in the lung and colon. B: After alcohol exposure, the mammary tumor tissues were assessed for the expression of phosphorylated ErbB2 (pErbB2) and p38γ MAPK (p-p38γ) by immunoblotting. The relative levels of pErbB2 and p-p38γ were quantified and normalized to the loading control. * denotes significant difference from control groups (p < 0.05). Alcohol consumption significantly increased the phosphorylation of ErbB2 and p38γ ([33].

Figure 2

Alcohol increases the cancer stem-like cell (CSC) population. A: Human breast cancer cell lines MCF7 or MCF7 overexpressing ErbB2 cells (MCF7-ErbB2) were exposed to alcohol (0 or 100 mg/dl) for 10 days, and then evaluated for CSCs by the ALDEFLUOR assay. * denotes significant difference from respective control groups. # denotes significant difference from alcohol-treated MCF7 cells. B: MCF7-ErbB2 cells were exposed to alcohol (0, 100 mg/dl) for 10 days and then mammosphere formation was evaluated under the microscope. C: MCF7, MCF7-ErbB2 or BT474 cells were exposed to alcohol (0, 100 mg/dl) for 10 days. The number of mammospheres was determined. * denotes significant difference from respective control groups. # denotes significant difference from alcohol-treated MCF7 cells. D: FVB MMTV Neu mice were fed with a liquid diet containing ethanol (0 or 6.7%). After alcohol exposure, the mammary tumor tissues were assessed for the expression of CD44. * denotes significant difference from respective control groups. Alcohol significantly increased CSC population in vitro and in vivo [33].

Figure 3

Alcohol stimulates the phosphorylation of ErbB2, FAK and cSrc. A: MCF7-ErbB2 cells were pretreated with alcohol for 48 hours and plated to fibronectin-coated coverslips, allowing attachment for 1 hour. Phosphorylation of FAK (Tyr861) and ErbB2 (Tyr1248) was detected with immunofluorescent staining. Arrows indicate the co-localization of pErbB2 and pFAK. B: MCF7-ErbB2 cells were pretreated with alcohol for 6–48 hours, and allowed to attach for 3 hours. Cell lysates were collected and analyzed for the phosphorylation of FAK and cSrc with immunoblotting. The relative levels of pFAK and pcSrc were quantified and normalized to the expression of FAK and cSrc, respectively. * denotes significant difference from respective control groups. Alcohol significantly increased the phosphorylation of ErbB2, FAK and cSrc [37].