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Background: The majority of women risk eligible for primary breast cancer prevention with tamoxifen or aromatase inhibitors refuse uptake due to concerns about side effects, especially vasomotor symptoms. Tamoxifen may also have detrimental metabolic effects in overweight/obese women. Duavee™, a complex of bazedoxifene (BZA) and conjugated estrogen (CE), is FDA approved for relief of hot-flashes and prevention of osteoporosis. Preclinical studies suggest favorable metabolic effects in ovariectomized animals and potential for breast cancer risk reduction. A single arm clinical trial found reduction in Ki-67 and mammographic density such that BZA+CE is being further evaluated in a Phase IIB trial of peri and early postmenopausal women with vasomotor symptoms who are at high risk for breast cancer. Here, in a companion study, we assessed the effect of BZA+ CE on metabolic health and cancer risk in a rat model of carcinogen induced ER+ tumors and high fat diet induced obesity. Methods: Rats received 50 mg/kg N-methylnitrosourea at 7 weeks to increase mammary tumor risk and were fed a high fat diet (46% kcal fat) to promote obesity. At 16 weeks lean and obese rat were selected based on % body fat and were then randomized to 8 weeks of daily oral vehicle control or 3mg BZA + 0.07mg CE/kg body weight. Systemic metabolic variables were measured at 16 and 24 weeks, and RNA from mammary glands analyzed by gene expression microarray (Affymetrix). Results: BZA+CE resulted in systemic as well as mammary changes indicative of improved metabolic health, including: reduction in total and visceral fat (p Conclusions: Unlike tamoxifen, BZA+CE improved whole body and mammary gland metabolic health, particularly in obese rats. Transcriptional profiling and GSEA demonstrated a blunting of cell cycle and proliferation and enrichment of metabolic and immune-related pathways. Together this supports BZA+CE (Duavee) as an agent to be explored for breast cancer risk reduction in obese individuals. Funding: This work was supported in part by P30 CA168524, R00 CA169430, and R25 CA203650. Citation Format: Ramsey M. Jenschke, Karen A. Corleto, Carol J. Fabian, Stephen D. Hursting, Bruce F. Kimler, Danilo Landrock, Tara N. Mahmood, Katherine L. Cook, Erin D. Giles. Bazedoxifene plus conjugated estrogen improves metabolic health and reduces mammary gland epithelial proliferation in an ovary intact rat model of obesity and breast cancer risk. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5259.

Obesity and adult weight gain are linked to increased breast cancer risk and poorer clinical outcomes in postmenopausal women, particularly for hormone-dependent tumors. Menopause is a time when significant weight gain occurs in many women, and clinical and preclinical studies have identified menopause (or ovariectomy) as a period of vulnerability for breast cancer development and promotion. We hypothesized that preventing weight gain after ovariectomy (OVX) may be sufficient to prevent the formation of new tumors and decrease growth of existing mammary tumors. Here, we tested this hypothesis in a rat model of obesity and carcinogen-induced postmenopausal mammary cancer and validated our findings in a murine xenograft model with implanted human tumors. In both models, preventing weight gain after OVX significantly decreased obesity-associated tumor development and growth. Importantly, we did not induce weight loss in these animals, but simply prevented weight gain. In both lean and obese rats, preventing weight gain reduced visceral fat accumulation and associated insulin resistance. Similarly, the intervention decreased circulating tumor-promoting growth factors and inflammatory cytokines (ie, BNDF, TNFα, FGF2), with greater effects in obese compared to lean rats. In obese rats, preventing weight gain decreased adipocyte size, adipose tissue macrophage infiltration, reduced expression of the tumor-promoting growth factor FGF-1, and reduced phosphorylated FGFR in tumors. Together, these findings suggest that the underlying mechanisms associated with the anti-tumor effects of weight maintenance are multifactorial, and that weight maintenance during the peri-/post-menopausal period may be a viable strategy for reducing obesity-associated breast cancer risk and progression in women.

The proposed analytical method reports the separation and quantification of 21 amino acids including l-citrulline from fresh vegetables and commercial juices using a C8 column. Optimal separation conditions for amino acids analysis were obtained with 20 mM sodium acetate (solvent A) and water with organic modifier acetonitrile and methanol (solvent B; 18/50/32 V/V). The ideal pH and column temperature were found to be 5.40 and 35 °C, respectively. The LOD and LOQ values were obtained in the range of 0.02–0.19 ng/mL and 0.04–0.39 ng/mL for all amino acids respectively. Relative standard deviations (RSD) of intraday and interday analysis were found to be

Nitrate and polyphenols from the diet may enhance the production and bioavailability of nitric oxide, a radical signaling molecule critical for cardiovascular health. Understanding the stability of these bioactives in beetroot and arugula juices is important for their functions. In this study, the stability of nitrate and phenolics in beetroot and arugula juices was measured for 32 days at different temperatures (25, 4, -20, and -80 °C). The levels of nitrate were measured by reversed-phase HPLC and initial levels were found to be 4965.34 ± 72.69 µg/mL for beetroot and 6310.20 ± 24.79 µg/mL for arugula. Interestingly, nitrate degradation started within 24 hr at 25 °C and after 4 days at 4 °C. At -20 °C and -80 °C, nitrate levels remained stable for one month. Total phenolics and free radical scavenging activity varied significantly during storage conditions. Beetroot juice at 25 °C, significant decrease in total phenolics and antioxidant activity was observed, whereas at 4, -20 and -80 °C, the levels remained relatively stable. By contrast, arugula juice at 25 and 4 °C, an increase in total phenolics and antioxidant activity were observed after one month. Furthermore, UPLC-HR-QTOF-MS analysis demonstrated that flavonoid glucosides were converted to their aglycones and lower phenolics, resulting in higher total phenolics and antioxidant activity during storage. In conclusion, beetroot and arugula juices required frozen conditions for long-term storage to prevent degradation of nitrate and to maintain their nutritional value. Beetroot and arugula juices have health-beneficial compounds such as nitrate and phenolics. Understanding the proper storage conditions can allow consumers to make informed choices that can help fresh juices to maintain their health promoting properties.

Introduction: Many women at high risk for breast cancer will not take standard selective estrogen receptor modulators (SERMs) for cancer prevention due to concern of side effects, especially vasomotor symptoms. Duavee®, a tissue selective complex of the SERM bazedoxifene (BZA; 20mg) + conjugated estrogen (CE; 0.45mg), is FDA approved for relief of hot-flashes. Preclinical and early phase human studies suggest Duavee® has potential for breast cancer prevention, with favorable change in mammographic fibroglandular volume and proliferation. Given the >40% incidence of obesity in postmenopausal women, and that obesity increases breast cancer risk, the current study was aimed at identifying the effects of obesity on response to Duavee® in a rodent model of obesity and postmenopausal breast cancer. Methods: This study used our well-characterized rat model of diet-induced obesity and postmenopausal ER-positive breast cancer. Rats were injected with N-methylnitrosourea (MNU, 50 mg/kg) at 7 weeks of age to induce mammary tumors and fed a high fat diet (HF; 46% kcal fat) to promote obesity. Lean and obese rat were selected based on % body fat at 16 weeks. Tumors were monitored by manual palpation weekly and measured using digital calipers. Tumor-bearing rats were ovariectomized (OVX) when a tumor reached 0.7cm3. Rats were then maintained on ad libitum HF diet or HF diet plus a daily oral dose of Duavee® (3mg BZA+ 0.07mg CE/kg body weight) for 8 weeks. Body composition was analyzed biweekly (qMR) and fat pads weighed at study end to determine regional fat distribution. Results: Like menopause in women, OVX induces weight gain in this model. Duavee® significantly blunted the OVX-induced weight gain in both lean (-65%, p Conclusions: These data suggest that Duavee® may provide beneficial effects on body composition and metabolism in obese OVX animals without promotion of tumor growth. Further analyses will include study of direct effects of Duavee® on tumors, the tumor microenvironment, and systemic markers of insulin resistance and mammary cancer risk in our rat model of pre-and postmenopausal obesity and breast cancer. Citation Format: Karen A. Corleto, Tara N. Mahmood, Danilo Landrock, Stephen D. Hursting, Carol J. Fabian, Bruce F. Kimler, Erin D. Giles. Duavee® improves metabolic health without increasing cancer risk: findings from a preclinical model of obesity and postmenopausal breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2567.

Nitrate and polyphenols from the diet may enhance the production and bioavailability of nitric oxide, a radical signaling molecule critical for cardiovascular health. Understanding the stability of these bioactives in beetroot and arugula juices is important for their functions. In this study, the stability of nitrate and phenolics in beetroot and arugula juices was measured for 32 days at different temperatures (25, 4, -20, and -80 °C). The levels of nitrate were measured by reversed-phase HPLC and initial levels were found to be 4965.34 ± 72.69 μg/mL for beetroot and 6310.20 ± 24.79 μg/mL for arugula. Interestingly, nitrate degradation started within 24 hr at 25 °C and after 4 days at 4 °C. At -20 °C and -80 °C, nitrate levels remained stable for one month. Total phenolics and free radical scavenging activity varied significantly during storage conditions. Beetroot juice at 25 °C, significant decrease in total phenolics and antioxidant activity was observed, whereas at 4, -20 and -80 °C, the levels remained relatively stable. By contrast, arugula juice at 25 and 4 °C, an increase in total phenolics and antioxidant activity were observed after one month. Furthermore, UPLC-HR-QTOF-MS analysis demonstrated that flavonoid glucosides were converted to their aglycones and lower phenolics, resulting in higher total phenolics and antioxidant activity during storage. In conclusion, beetroot and arugula juices required frozen conditions for long-term storage to prevent degradation of nitrate and to maintain their nutritional value.Beetroot and arugula juices have health-beneficial compounds such as nitrate and phenolics. Understanding the proper storage conditions can allow consumers to make informed choices that can help fresh juices to maintain their health promoting properties.