Abstract P6-15-04: Modeling limited breastfeeding and diet on IBC like tumor progression

Abstract

Abstract Introduction/Motivation: We previously reported IBC patients with limited breast-feeding history have a worse prognosis than those with greater breast feeding history. Further, we reported pregnancy related factors including multiple early pregnancies and not breast feeding as well as obesity are risk factors for triple negative and ER+ subtypes. Significant evidence suggests the microenvironment drives IBC symptoms and growth pattern. We sought to characterize the impact of purported risk factors on tumor growth, IBC-like skin symptoms and mammary gland microenvironment in animal models. Methods: We commissioned breeding of nulliparous, multiparous (x 2) force weaned, and multiparous naturally weaned (labeled nursing) mice. Mice in each of the three groups were fed either a low fat (10 Kcal %) or high fat (60 Kcal %) diet for three weeks before tumor cell injections. SUM 149 GFP Luc were injected into the left ventral #4 mammary fat pad. Mice were sacrificed, scored for the IBC-like symptom of gross skin invasion or evident skin symptoms, and tissue from the contralateral mammary gland were sectioned and stained with H and E. Analysis was performed on the 31 animals that developed primary tumors and were scored for skin invasion at the time of resection. Of these 26 mice had contralateral gland tissue assessed by H and E. Phenotypes including duct dilation, degree of adipose tissue, duct density, inflammation and necrosis were scored manually, 1-3 scale. Quadratic mixed models with random intercept were fitted to compare tumor growth. Fisher’s exact test and T-tests were performed to compare variables. Results: Tumor incidence and latency were not different by risk factor group. Tumor growth was faster in multiparous force weaned versus others, P < 0.0001, but unchanged by diet, P = 0.187. Force weaned animals on a high fat diet had a trend for increased skin invasion compared to others (force weaned high fat diet vs. other 85% vs. 42%; P = 0.08) suggesting a synergy for this IBC-like symptom. Contralateral gland ductal density (less dense) and ductal dilation (not dilated) were normal histologic variables which correlated with skin invasion on the tumor side (P =0.006 and P = 0.011, respectively). Gland density but not dilated ducts trended to correlation with force weaning, P = 0.07, but not diet. Discussion: In this effect size finding pilot study, combined risk factors were associated with a higher incidence of skin invasion of SUM149 xenografts. Changes in the microenvironment in the contralateral gland typical of involution were significantly associated with skin invasion, and gland density trends towards association with force weaning. These data provide provocative pilot results linking histologic effects in the microenvironment to tumor growth characteristics and support the hypothesis that involution induced by forced weaning may facilitate IBC-like tumor growth. These studies facilitate well-powered additional work to establish mechanism and automate normal tissue evaluation. Citation Format: Wintana Balema, Richard Larson, Renae Van Whye, Rong Ye, Jing Ning, Omar Rahal, Shane Stecklein, Savitri Krishnamurthy, Randa El-Zein, Wendy Woodward. Modeling limited breastfeeding and diet on IBC like tumor progression [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-15-04.