Abstract 4685: Caffeine and caffeic acid inhibit growth and modify estrogen receptor (ER)-α and insulin-like growth factor I receptor (IGF-IR) levels in human breast cancer
Authors: Rosendahl Ann H. , Perks Claire M. , Markkula Andrea , Simonsson Maria , Rose Carsten C. , Ingvar Christian , Holly Jeff M. , Jernström Helena 
Published: May 2015

Abstract
Estrogen receptor (ER)-α is critically involved in breast cancer development, progression and disease management. Emerging evidence indicate that epigenetic and non-epigenetic mechanisms may be a frequent cause for loss of ERα during tumor progression, which in turn may be modifiable by dietary and lifestyle factors. In line with epidemiological reports on chemopreventive effects by coffee on breast cancer risk and prognosis, we assessed the influence of coffee consumption on tumor characteristics in an extended cohort of 1090 patients with invasive primary breast cancer in southern Sweden, aged 24-99 years, with preoperatively reported daily coffee consumption. Moderate (2-4 cups/day) to high (5+ cups/day) daily coffee intake were associated with significantly smaller invasive primary tumor sizes (Ptrend = 0.013), while concomitantly lower frequency of ER+ tumors (Ptrend = 0.018), compared to women with low coffee consumption (≤1 cup/day). To establish how coffee intake may alter molecular mechanisms with impact on breast cancer growth in relation to ER status, we extended our clinical observations to in vitro models of ER+ (MCF-7) and ER- (MDA-MB-231) human breast cancer cells. Exposure to the coffee constituents caffeine and caffeic acid significantly suppressed the proliferation of both ER+ (by 59% and 38%, respectively) and ER- (by 47% and 28%, respectively) human breast cancer cells. In line with the clinical observations, the ER+ breast cancer cells appeared more sensitive to the growth inhibitory effects by the coffee constituents compared to ER- cells. The antiproliferative actions were associated with altered ER levels. We found that caffeine destabilized ERα and reduced ERα abundance in ER+ cells, while caffeine and caffeic acid enabled re-expression of ERα in ER- cells, both resulting in growth inhibition. In addition, caffeine reduced the levels of the mitogenic insulin-like growth factor type I receptor (IGF-IR) in both ER+ and ER- breast cancer cells. Together the effects by caffeine and caffeic acid on ER and IGF-IR abundance with impact on downstream effectors, resulted in impaired G1 to S transition with incapacity to complete the cell cycle and enhanced cell death. In summary, this study demonstrate multiple anticancer properties of caffeine and caffeic acid against both ERα-positive and ERα-negative breast cancer in vitro that may sensitize tumor cells to current endocrine therapies. Together these experimental and clinical findings provide a more comprehensive understanding of the functional and mechanistic effects of these dietary factors that can modify cancer progression.
Citation Format: Ann H. Rosendahl, Claire M. Perks, Andrea Markkula, Maria Simonsson, Carsten C. Rose, Christian Ingvar, Jeff MP Holly, Helena Jernström. Caffeine and caffeic acid inhibit growth and modify estrogen receptor (ER)-α and insulin-like growth factor I receptor (IGF-IR) levels in human breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4685. doi:10.1158/1538-7445.AM2014-4685