Obesity is Positively Correlated with DNA Damage in Breast Epithelium of BRCA Mutation Carriers in Association with Adipose Inflammation and Elevated Aromatase Expression
Presentation Number: OR18-2
Date of Presentation: March 18, 2018, 2018
Priya Bhardwaj, BA1, Heba Zahid, MS2, Neil M. Iyengar, MD3, Xi Kathy Zhou, PhD1, Dilip D. Giri, MD3, I-Chun Chen, MD1, Monica Morrow, MD3, Clifford A. Hudis, MD3, Andrew J. Dannenberg, MD1, Kristy A. Brown, PhD1.
1Weill Cornell Medicine, New York, NY, USA, 2Hudson Institute of Medical Research, Clayton, Australia, 3Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Obesity is a well-established risk factor breast cancer. Studies have also reported a greater incidence of breast cancer in BRCA mutation carriers who are obese compared with BRCA mutation carriers who are lean. Molecular mechanisms that explain the increased penetrance of breast cancer in obese women are poorly understood. We hypothesized that obesity-associated dysfunctional adipose tissue, inclusive of local inflammation, as well as aromatase, the rate-limiting enzyme for estrogen biosynthesis, may play a role in causing breast epithelium DNA damage, a known driver of tumorigenesis. Furthermore, carrying a BRCA mutation may enhance DNA damage even further due to dysfunctional DNA repair ability caused by the mutation. To test this hypothesis, DNA damage was assessed in breast FFPE sections from BRCA mutation carriers and wildtype individuals by immunofluorescence (IF) staining of DNA repair markers ƴH2AX and 53BP1. We found that obesity was positively associated with DNA damage in breast epithelial cells in both wildtype individuals (p<0.05) and BRCA mutation carriers (p<0.01) with a stronger effect seen in BRCA mutation carriers (20% increase in DNA damage vs 100% increase when comparing lean vs obese, respectively). Conditioned media from obese breast adipose tissue explants and isolated adipocytes significantly induced DNA damage in MCF-10A breast epithelial cells (p<0.01), suggesting a role of obese adipose tissue and specifically adipocytes in driving DNA damage. Additionally, obesity-induced breast adipose inflammation, quantified as crown-like structures (CLS) per cm2, and aromatase expression were both positively associated with DNA damage among BRCA mutation carriers (p<0.01). Using a mouse model of obesity, we found that high fat diet was strongly associated with mammary gland DNA damage (r=0.66, p<0.01) and caloric restriction, which resulted in a decrease in inflammation and aromatase levels, was sufficient to significantly decrease DNA damage even after high fat diet feeding (p<0.05). These data show for the first time that obesity is associated with increased DNA damage in breast epithelium of BRCA mutation carriers. Our results suggest that therapies targeting local inflammation and/or estrogen production may reduce the elevation in DNA damage observed in obese BRCA mutation carriers and thereby decrease tumor formation in this high-risk population of women.
P. Bhardwaj: None. H. Zahid: None. N.M. Iyengar: None. X. Zhou: None. D.D. Giri: None. I. Chen: None. M. Morrow: None. C.A. Hudis: None. A.J. Dannenberg: None. K.A. Brown: None.