Exploring Molecular and Morphological Relationships between Obesity and CtBP in Breast Cancer
Authors: Park Samson , Yan Tingfen , Crawford Lindsey , Li Daniel , Jones Alana , Caban Ambar , Gil‐Hernandez Sara , Kabbout Mohamed , Yi Dae Ik , Ambs Stefan , Periwal Vipul , Byun Jung S. , Gardner Kevin 
Published: November 2023

In the United States, more than 70% of adults are either overweight or obese. This epidemic is associated with grave health consequences, including cardiovascular diseases, kidney diseases, and cancer. One possible mechanism accounting for these risks is metabolic imbalance associated with obesity. Currently, the most common method of quantifying metabolic imbalance is by measuring a person's body mass index (BMI), an effective but incomplete measurement that only takes into account the overall height and weight. An approach that may complement the quantification of obesity‐induced metabolic imbalance is directly examining adipocyte size distribution around the tumors. After adolescence, the adipose cell number remains relatively steady, and the excess energy storage is primarily accomplished through adipocyte hypertrophy; however, after prolonged obesity and continuous positive energy balance, the adipocytes begin to undergo hyperplasia to increase their number. Therefore, we believe the state of obesity with a high level of adipocyte hyperplasia may represent the worst prognostic case of metabolic imbalance. Because 70% of human breast is composed of adipose tissue, this is especially relevant for breast cancer. Furthermore, a key molecule that may work in conjunction with obesity to worsen breast cancer prognosis is C‐terminal binding protein (CtBP), a dimeric nuclear protein that plays a substantial epigenetic role in modifying gene expression by inducing Epithelial‐Mesenchymal Transition, genome instability, and stem cell‐like pathways. What makes CtBP metabolically relevant is that its activity depends on NADH, a prominent byproduct of metabolism that is elevated under conditions of obesity, diabetes, and metabolic syndrome. When NADH binds to CtBP, CtBP is able to dimerize, improve its stability, and enhance its nuclear localization. For this reason, we think CtBP may be a key metabolic sensor that connects modifiable risk factors like obesity to molecular pathways of breast cancer.

In this study, we explore a link between obesity and CtBP by examining cohorts of breast cancer patient samples. Using digital analysis of histological sections and immunohistochemistry, we first measure adipocyte cross‐sectional area and obtain CtBP protein expression for each patient. We analyze and correlate the adipocyte size distribution and BMI with gene and protein expression of CtBP. Our preliminary results demonstrate that obesity measured by BMI exacerbates a poor breast cancer patient outcome driven by high protein level of CtBP alone. Our data also suggest that breast cancer patients with high BMI and excessive hyperplasia have significantly poorer survival and higher protein expression of CtBP. The results of this study provide new approaches to understanding how aspects of lifestyle and personal traits may interact with the molecular pathways of CtBP to influence breast cancer incidence and mortality.