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Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-Like Growth Factor I Receptor Levels in Human Breast Cancer Ann H

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Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-Like Growth Factor I Receptor Levels in Human Breast Cancer Ann H Published OnlineFirst February 17, 2015; DOI: 10.1158/1078-0432.CCR-14-1748 Cancer Therapy: Clinical Clinical Cancer Research Caffeine and Caffeic Acid Inhibit Growth and Modify Estrogen Receptor and Insulin-like Growth Factor I Receptor Levels in Human Breast Cancer Ann H. Rosendahl1, Claire M. Perks2, Li Zeng2, Andrea Markkula1, Maria Simonsson1, Carsten Rose3, Christian Ingvar4, Jeff M.P. Holly2, and Helena Jernstrom€ 1 Abstract Purpose: Epidemiologic studies indicate that dietary factors, 0.018), compared with patients with low consumption (1 cup/ such as coffee, may influence breast cancer and modulate hor- day). Moderate to high consumption was associated with lower þ mone receptor status. The purpose of this translational study was risk for breast cancer events in tamoxifen-treated patients with ER to investigate how coffee may affect breast cancer growth in tumors (adjusted HR, 0.51; 95% confidence interval, 0.26–0.97). þ relation to estrogen receptor-a (ER) status. Caffeine and caffeic acid suppressed the growth of ER (P 0.01) À Experimental Design: The influence of coffee consumption on and ER (P 0.03) cells. Caffeine significantly reduced ER and þ patient and tumor characteristics and disease-free survival was cyclin D1 abundance in ER cells. Caffeine also reduced the assessed in a population-based cohort of 1,090 patients with insulin-like growth factor-I receptor (IGFIR) and pAkt levels in þ À invasive primary breast cancer in Sweden. Cellular and molecular both ER and ER cells. Together, these effects resulted in impaired effects by the coffee constituents caffeine and caffeic acid were cell-cycle progression and enhanced cell death. þ À evaluated in ER (MCF-7) and ER (MDA-MB-231) breast cancer Conclusion: The clinical and experimental findings demon- cells. strate various anticancer properties of caffeine and caffeic acid þ À Results: Moderate (2–4 cups/day) to high (5 cups/day) against both ER and ER breast cancer that may sensitize tumor coffee intake was associated with smaller invasive primary tumors cells to tamoxifen and reduce breast cancer growth. Clin Cancer Res; þ (Ptrend ¼ 0.013) and lower proportion of ER tumors (Ptrend ¼ 21(8); 1–11. Ó2015 AACR. Introduction gression is the loss of the estrogen receptor-a (ER), which is associated with a more aggressive tumor phenotype and the loss Breast cancer is the major cancer affecting women with a of sensitivity to endocrine therapies such as tamoxifen (3). ER can lifetime risk of more than 10% in the general population in stimulate cellular proliferation via progesterone receptor (PgR) Western countries. The prevalence is, however, much lower in induction and transcriptional upregulation of cyclin D1, leading Asia and many economically developing countries (1). However, to enhanced cell-cycle progression, whereas ER loss has been Asian immigrants to the United States acquire the prevalence of associated with enhanced motility and metastatic abilities of that country within one generation, indicating a strong effect of breast cancer cells. Although loss of ER activity and expression environmental exposures. Although the majority of primary has critical consequences for breast cancers, it generally occurs breast cancer is estrogen-driven and often responsive to endocrine without evidence of ER gene mutation or deletion. Alterations in treatment, many patients progress to estrogen-insensitive disease ER levels can be regulated at transcriptional or posttranscriptional with poor prognosis (2, 3). A critical determinant of such pro- stages, or through epigenetic mechanisms (4). Given that the prevalence of breast cancer varies between different geographic locations, potential modifiable environmental, dietary, and life- 1Lund University and Ska ne University Hospital, Department of Clinical style determinants may also influence the ER status. Sciences, Lund, Division of Oncology and Pathology, Lund, Sweden. The insulin-like growth factor (IGF) family has been identified 2University of Bristol, School of Clinical Sciences, IGFs and Metabolic Endocrinology Group, Southmead Hospital, Bristol, United Kingdom. as an additional driver of breast cancer. The mitogenic and 3Lund University, CREATE Health and Department of Immunotech- antiapoptotic signals are mediated via the IGF type I receptor nology, Medicon Village, Lund, Sweden. 4Lund University and Skane (IGFIR) and its downstream targets MAPK–ERK or PI3K–Akt. The University Hospital, Department of Clinical Sciences, Lund, Division of ER and IGFIR signaling systems are tightly linked and subject to Surgery, Lund, Sweden. feedback cross-talk. For example, estrogen and IGFs coregulate Note: Supplementary data for this article are available at Clinical Cancer several genes that affect breast cancer outcome (5). In addition, Research Online (http://clincancerres.aacrjournals.org/). hyperactive IGFIR–PI3K–Akt signaling has been implicated to Corresponding Author: Ann H. Rosendahl, Lund University and Skane University contribute in the acquisition of resistance to endocrine therapy Hospital, Barngatan 2B, SE-221 85 Lund, Sweden. Phone: 46-46-17-7567; Fax: during breast cancer progression (6). Estrogen increases IGFIR 46-46-14-7327; E-mail: [email protected] mRNA and antiestrogens, like tamoxifen, can reduce serum IGFI doi: 10.1158/1078-0432.CCR-14-1748 levels and IGF-mediated growth (7, 8). Conversely, blocking IGF Ó2015 American Association for Cancer Research. actions can inhibit estrogen-mediated growth (9). Similar to ER www.aacrjournals.org OF1 Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2015 American Association for Cancer Research. Published OnlineFirst February 17, 2015; DOI: 10.1158/1078-0432.CCR-14-1748 Rosendahl et al. anti-IGFIRb (C-20) was purchased from Santa Cruz Biotechnol- Translational Relevance Ser473 ogy; anti–phospho-Akt (#4060), anti-Akt (#9272), anti–Bcl- Despite improved diagnostic and treatment modalities, 2 (#2870), anti–Bcl-xL (#2764), anti-cleaved caspase-7 (#9491), breast cancer remains the leading cause of cancer-related death anti-cleaved PARP (#9541), anti-cyclin D1 (#2926), and anti– among women worldwide. An increased understanding of the glyceraldehyde-3-phosphate dehydrogenase (GAPDH, #3683) clinical and mechanistic effects of modifiable components of were purchased from Cell Signaling Technology Inc. our daily diet on breast cancer characteristics and prognosis could lead to better patient information for managing disease. Study population This study reveals that increasing coffee consumption is The present study is based on an extended cohort of 1,090 associated with significantly smaller invasive breast tumor women, ages 24 to 99 years, diagnosed with primary invasive þ sizes, a lower proportion of ER tumors, and improved dis- breast cancer between October 2002 and December 2012 at the þ ease-free survival among tamoxifen-treated women with ER Skane University Hospital (Lund, Sweden), without preoperative breast cancer. Mechanistically, this study shows that predom- treatment and with no other cancer history within the past 10 inantly caffeine, but also caffeic acid, mimics the actions of years. This is an ongoing cohort (BC Blood study) and is now antiestrogens and modifies major growth regulatory pathways updated to include almost twice as many women as recently ER/cyclin D1 and IGFIR/pAkt, resulting in impaired cell-cycle reported by our group (17). The inclusion and exclusion criteria progression and reduced cellular proliferation. Together, these were compliant to the REporting recommendations for tumor translational findings provide a more comprehensive under- MARKer prognostic study (REMARK) guidelines (18). During the standing of the clinical and mechanistic effects of these dietary preoperative visit, body measurements of weight, height, waist factors that can modify breast cancer progression. and hip circumference, and breast volume were collected (as previously described; refs. 19, 20). Extensive questionnaire data with information on reproductive factors, the use of exogenous hormones or other medications, lifestyle factors, including smok- activity, various anthropometric, lifestyle, and dietary factors can ing, alcohol, and coffee consumption, etc., were obtained from influence the IGF system with impact on cancer development and the cohort members at the preoperative visit. Information on progression. tumor size, lymph node status, histologic grade, proliferative In recent years, mechanisms involved in mediating cancer index (Ki67), and hormone receptor status (ER and PgR) were a chemopreventive effects of naturally derived plant polyphenols obtained through pathology reports and medical records. ER from green tea and coffee have been widely studied in several status was routinely determined until December 2009, using neoplasias, including breast and prostate cancer (10–13). How- antibody clone 1D5 (DAKO), and from 2010 using clone SP1 ever, there have been few translational studies on anticancer (Ventana Medical Systems), as previously described (17, 21). effects of coffee in relation to ER status in breast cancer. Prospec- Follow-up information of breast cancer recurrence or death was tive and retrospective epidemiologic studies show an association obtained from patient charts, pathology reports, the Regional between coffee consumption and a significantly reduced risk, Tumor Registry or the Population Registry. Written informed delayed onset, and reduced growth of breast cancer (14, 15). consents were obtained from all participating
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