Purpose: Epidemiologic studies indicate that dietary factors, such as coffee, may influence breast cancer and modulate hormone receptor status. The purpose of this translational study was to investigate how coffee may affect breast cancer growth in relation to estrogen receptor-α (ER) status. Experimental Design: The influence of coffee consumption on patient and tumor characteristics and disease-free survival was assessed in a population-based cohort of 1,090 patients with invasive primary breast cancer in Sweden. Cellular and molecular effects by the coffee constituents caffeine and caffeic acid were evaluated in ER⁺ (MCF-7) and ER⁻ (MDA-MB-231) breast cancer cells. Results: Moderate (2–4 cups/day) to high (≥5 cups/day) coffee intake was associated with smaller invasive primary tumors (P_trend = 0.013) and lower proportion of ER⁺ tumors (P_trend = 0.018), compared with patients with low consumption (≤1 cup/day). Moderate to high consumption was associated with lower risk for breast cancer events in tamoxifen-treated patients with ER⁺ tumors (adjusted HR, 0.51; 95% confidence interval, 0.26–0.97). Caffeine and caffeic acid suppressed the growth of ER⁺ (P ≤ 0.01) and ER⁻ (P ≤ 0.03) cells. Caffeine significantly reduced ER and cyclin D1 abundance in ER⁺ cells. Caffeine also reduced the insulin-like growth factor-I receptor (IGFIR) and pAkt levels in both ER⁺ and ER⁻ cells. Together, these effects resulted in impaired cell-cycle progression and enhanced cell death. Conclusions: The clinical and experimental findings demonstrate various anticancer properties of caffeine and caffeic acid against both ER⁺ and ER⁻ breast cancer that may sensitize tumor cells to tamoxifen and reduce breast cancer growth. Clin Cancer Res; 21(8); 1877–87. ©2015 AACR.

Background: Epidemiological studies have shown direct associations between type 2 diabetes and obesity, both conditions associated with hyperglycaemia and hyperinsulinemia, and the risk of pancreatic cancer. Up to 80% of pancreatic cancer patients present with either new-onset type 2 diabetes or impaired glucose tolerance at the time of diagnosis. Recent population studies indicate that the incidence of pancreatic cancer is reduced among diabetics taking metformin. In this study, the effects of exposure of pancreatic cancer cells to high glucose levels on their growth and response to metformin were investigated. Methods: The human pancreatic cancer cell lines AsPC-1, BxPC-3, PANC-1 and MIAPaCa-2 were grown in normal (5 mM) or high (25 mM) glucose conditions, with or without metformin. The influence by metformin on proliferation, apoptosis and the AMPK and IGF-IR signalling pathways were evaluated in vitro. Results: Metformin significantly reduced the proliferation of pancreatic cancer cells under normal glucose conditions. Hyperglycaemia however, protected against the metformin-induced growth inhibition. The anti-proliferative actions of metformin were associated with an activation of AMP-activated protein kinase AMPK^Thr172 together with an inhibition of the insulin/insulin-like growth factor-I (IGF-I) receptor activation and downstream signalling mediators IRS-1 and phosphorylated Akt. Furthermore, exposure to metformin during normal glucose conditions led to increased apoptosis as measured by poly(ADP-ribose) polymerase (PARP) cleavage. In contrast, exposure to high glucose levels promoted a more robust IGF-I response and Akt activation which correlated to stimulated AMPK^Ser485 phosphorylation and impaired AMPK^Thr172 phosphorylation, resulting in reduced anti-proliferative and apoptotic effects by metformin. Conclusion: Our results indicate that metformin has direct anti-tumour activities in pancreatic cancer cells involving AMPK^Thr172 activation and suppression of the insulin/IGF signalling pathways. However, hyperglycaemic conditions enhance the insulin/IGF-I responses resulting in an altered AMPK activation profile and prevent metformin from fully switching off the growth promoting signals in pancreatic cancer cells.

Vitamin D has been suggested to prevent and improve the prognosis of several cancers, including breast cancer. We have previously shown a U-shaped association between pre-diagnostic serum levels of vitamin D and risk of breast cancer-related death, with poor survival in patients with the lowest and the highest levels respectively, as compared to the intermediate group. Vitamin D exerts its functions through the vitamin D receptor (VDR), and the aim of the current study was to investigate if the expression of VDR in invasive breast tumors is associated with breast cancer prognosis. VDR expression was evaluated in a tissue microarray of 718 invasive breast tumors. Covariation between VDR expression and established prognostic factors for breast cancer was analyzed, as well as associations between VDR expression and breast cancer mortality. We found that positive VDR expression in the nuclei and cytoplasm of breast cancer cells was associated with favorable tumor characteristics such as smaller size, lower grade, estrogen receptor positivity and progesterone receptor positivity, and lower expression of Ki67. In addition, both intranuclear and cytoplasmic VDR expression were associated with a low risk of breast cancer mortality, hazard ratios 0.56 (95% CI 0.34–0.91) and 0.59 (0.30–1.16) respectively. This study found that high expression of VDR in invasive breast tumors is associated with favorable prognostic factors and a low risk of breast cancer death. Hence, a high VDR expression is a positive prognostic factor.

PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms. PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis. RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group. CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.

Being physically active as part of everyday life reduces breast cancer risk. Less is known whether the benefits of an active lifestyle differ depending on the timing of physical activity in life or anthropometric characteristics. The aim of this study was to bring further insights to the association of physical activity in relation to menopausal status and body composition with breast cancer risk by making use of a prospective Swedish cohort (Malmö Diet and Cancer Study) with long-term follow-up. Physical activity information of 15,983 participants for the past 12 months prior to study entry was assessed according to metabolic equivalent task (MET)-hours/week to integrate duration and intensity of reported activities. During 23.2 years median follow-up, 1302 invasive breast cancers occurred. Women reporting a high physical activity at study baseline, corresponding to >1 h daily walking/week (≥28.5 MET-h/week), had a 23% lower long-term breast cancer risk (HR_adj = 0.77, 95% CI 0.66–0.90) than those reporting low physical activity, being most pronounced among perimenopausal and postmenopausal women, and women with waist circumference, body fat percentage, or BMI in the upper-normal and overweight range. For premenopausal women or women having obesity or the largest body composition, high physical activity alone did not modify the breast cancer risk, suggesting additional preventive measures indicated in these groups to reduce the long-term risk of breast cancer.

Pancreatic cancer is associated with a highly abundant stroma and low-grade inflammation. In the local tumour microenvironment, elevated glucose levels, the presence of tumour-associated stellate cells and macrophages are hypothesised to promote the tumour progression and invasion. The present study investigated the influence by the microenvironment on pancreatic cancer cell invasion in vitro. After co-culture with tumour-associated pancreatic stellate cells (TPSCs), pancreatic cancer cells displayed up to 8-fold reduction in levels of epithelial-mesenchymal transition (EMT) markers E-cadherin and ZO-1, while β-catenin and vimentin levels were increased. A 3D organotypic model showed that TPSCs stimulated pancreatic cancer cell invasion, both as single cell (PANC-1) and cohort (MIAPaCa-2) invasion. The combined presence of TPSCs and M2-like macrophages induced invasion of the non-invasive BxPC-3 cells. High glucose conditions further enhanced changes in EMT markers as well as the cancer cell invasion. In summary, co-culture with TPSCs induced molecular changes associated with EMT in pancreatic cancer cells, regardless of differentiation status, and the organotypic model demonstrated the influence of microenvironmental factors, such as glucose, stellate cells and macrophages, on pancreatic cancer cell invasion.