Obesity and Breast Cancer Metastasis across Genomic Subtypes

Background: Obese women have higher risk of aggressive breast tumors and distant metastasis. However, obesity has rarely been assessed in association with metastasis in diverse populations. Methods: In the Carolina Breast Cancer Study Phase 3 (2008–2013), waist-to-hip ratio (WHR), body mass index (BMI), and molecular subtype [PAM50 risk-of-recurrence (ROR) score] were assessed. Obesity measures were evaluated in association with metastasis within five years of diagnosis, overall and stratified by race and ROR score. Absolute risk of metastasis and risk differences between strata were calculated using the Kaplan–Meier estimator, adjusted for age, grade, stage, race, and ER status. Relative frequency of metastatic site and multiplicity were estimated in association with obesity using generalized linear models. Results: High-WHR was associated with higher risk of metastasis (5-year risk difference, RD, 4.3%; 95% confidence interval, 2.2–6.5). It was also associated with multiple metastases and metastases at all sites except brain. The 5-year risk of metastasis differed by race (11.2% and 6.9% in Black and non-Black, respectively) and ROR score (19.5% vs. 6.6% in high vs. low-to-intermediate ROR-PT). Non-Black women and those with low-to-intermediate ROR scores had similar risk in high- and low-WHR strata. However, among Black women and those with high ROR, risk of metastasis was elevated among high-WHR (RDBlack/non-Black = 4.6%, RDHigh/Low-Int = 3.1%). Patterns of metastasis were similar by BMI. Conclusions: WHR is associated with metastatic risk, particularly among Black women and those with high-risk tumors. Impact: Understanding how risk factors for metastasis interact may help in tailoring care plans and surveillance among patients with breast cancer

Separate and combined effects of advanced age and obesity on mammary adipose inflammation, immunosuppression and tumor progression in mouse models of triple negative breast cancer

Introduction: Advanced age and obesity are independent risk and progression factors for triple negative breast cancer (TNBC), which presents significant public health concerns for the aging population and its increasing burden of obesity. Due to parallels between advanced age- and obesityrelated biology, particularly adipose inflammation, we hypothesized that advanced age and obesity each accelerate mammary tumor growth through convergent, and likely interactive, mechanisms. Methods: To test this hypothesis, we orthotopically transplanted murine syngeneic TNBC cells into the mammary glands of young normoweight control (7 months), young diet-induced obese (DIO), aged normoweight control (17 months), and aged DIO female C57BL/6J mice. Results: Here we report accelerated tumor growth in aged control and young DIO mice, compared with young controls. Transcriptional analyses revealed, with a few exceptions, overlapping patterns of mammary tumor inflammation and tumor immunosuppression in aged control mice and young DIO mice, relative to young controls. Moreover, aged control and young DIO tumors, compared with young controls, had reduced abundance ofcytotoxic CD8 T cells. Finally, DIO in advanced age exacerbated mammary tumor growth, inflammation and tumor immunosuppression. Discussion: These findings demonstrate commonalities in the mechanisms driving TNBC in aged and obese mice, relative to young normoweight controls. Moreover, we found that advanced age and DIO interact to accelerate mammary tumor progression. Given the US population is getting older and more obese, age- and obesity-related biological differences will need to be considered when developing mechanism-based strategies for preventing or controlling breast cancer

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumoradjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma (PPARG) visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between PPARG visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelialto-mesenchymal transition-as in fibrosis and metastasisand genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandinendoperoxide synthase 2 (PTGS2) colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high PTGS2 expression in colorectal tumors is significantly associated with higher concentrations of serum amyloidAand glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted

Régulation de l'IGF-I par la nutrition: mécanismes et implications

L’IGF-I (Insulin-like Growth Factor I) est un facteur de croissance indispensable à la croissance staturopondérale. L’IGF-I présent dans la circulation est essentiellement d’origine hépatique. Sa production est stimulée par l’hormone de croissance et régulée par la nutrition. En effet, la réduction de l’apport alimentaire diminue les taux circulants d’IGF-I. Les mécanismes responsables de la régulation de la production d’IGF-I par l’apport alimentaire, notamment en protéines, ont été largement caractérisés. Le contrôle de la production d’IGF-I par l’apport nutritionnel a permis d’imaginer un mécanisme par lequel la nutrition est capable de réguler les grandes fonctions physiologiques et peut contribuer au développement de certaines pathologies. Ainsi, le retard de croissance causé par la malnutrition protéinocalorique est en partie secondaire à une réduction des taux circulants d’IGF-I. Outre le retard de croissance, la réduction de l’apport nutritionnel induit également un allongement de la durée de vie dans de nombreuses espèces. De façon surprenante, l’inhibition de l’activité d’IGF-I obtenue par des manipulations génétiques s’accompagne elle aussi d’un allongement de la durée de vie. Il est dès lors possible que la réduction des taux d’IGF-I induite par la diminution de l’apport alimentaire contribue à l’allongement de la durée de vie observé. Contrairement à la malnutrition, un apport alimentaire excessif est susceptible d’augmenter, bien que modestement, les taux circulants d’IGF-I. Sur cette base, il a été suggéré que les taux d’IGF-I élevés observés dans l’obésité pourraient contribuer au risque accru de cancer observé dans cette population. En conclusion, les variations d’IGF-I circulante induites par des changements de l’apport nutritionnel pourraient affecter la croissance staturopondérale, la longévité et le risque de cancer