Principal Investigator

Kristy
Brown
Awardee Organization

Weill Medical Coll Of Cornell Univ
United States

Fiscal Year
2021
Activity Code
R01
Early Stage Investigator Grants (ESI)
Not Applicable
Project End Date

Obesity Increases Breast Cancer Penetrance in BRCA Mutation Carriers: A Role for Local and Systemic Factors

Mutant BRCA1 and BRCA2 DNA repair enzymes are causally linked to an increased risk of breast and ovarian cancers. Recent evidence suggests that cancers occur at these hormone-sensitive sites, at least in part, due to the pro-proliferative and mutagenic effects of estrogens. We reported that women who are obese have elevated levels of aromatase, the rate-limiting enzyme for estrogen production, in inflamed breast adipose tissue. This would be predicted to lead to increased local production of estrogen and may explain why obese postmenopausal women are at increased risk of developing hormone receptor-positive breast cancer. Obesity has been reported to increase the penetrance of breast cancer in BRCA1/2 mutation carriers. A major and potentially transformative research challenge is determining whether our discovery of the obesity-inflammation-aromatase link is important in the pathogenesis of breast cancer in BRCA1/2 mutation carriers. We now have possibly fieldchanging preliminary data which suggest that acquired characteristics, such as obesity and adipose inflammation, are associated with increased expression of aromatase in breast adipose stromal cells (ASCs) and an associated increase in DNA damage in the normal breast epithelium of BRCA mutation carriers. In this proposal, we will test the hypothesis that obesity, and associated breast white adipose tissue inflammation (WATi), will increase breast cancer penetrance in BRCA mutation carriers via local and systemic effects, including higher estrogen and insulin levels, that will lead to DNA damage in the breast epithelium and increase tumor burden. This hypothesis will be tested by first investigating whether an association exists between obesity, breast WATi and increased levels of systemic factors (e.g., estrogens, insulin, leptin, IL-6) in BRCA1/2 mutation carriers (Aim 1). Then, we will assess correlations between body mass index (BMI), breast WATi, estrogens and DNA damage in normal appearing breast epithelium (Aim 2). Given the importance of estrogens in the pathogenesis of hereditary breast cancer, we will next characterize mechanisms of aromatase regulation in breast adipose stromal cells of BRCA mutation carriers (Aim 3). Finally, we will utilize mouse models to determine whether suppressing estrogen biosynthesis can reduce mammary gland DNA damage and increase tumor latency, while also exploring whether a lifestyle intervention, i.e. reduction in caloric intake, or pharmacological intervention, i.e. use of the anti-diabetic drug metformin, can prevent these cancer-promoting changes (Aim 4). By focusing on the potential link between estrogen, DNA damage and breast cancer, this study promises to provide insights into why obesity increases the penetrance of breast cancer in BRCA1/2 mutation carriers. Importantly, results in this high risk population could prove relevant for understanding the mechanisms underlying the obesity-cancer connection for sporadic breast cancer. Finally, our findings should strengthen the rationale for evidence-based risk reduction strategies.

Publications

  • Brown KA. Metabolic pathways in obesity-related breast cancer. Nature reviews. Endocrinology. 2021 Jun;17(6):350-363. Epub 2021 Apr 29. PMID: 33927368
  • Reiterer M, Rajan M, Gómez-Banoy N, Lau JD, Gomez-Escobar LG, Ma L, Gilani A, Alvarez-Mulett S, Sholle ET, Chandar V, Bram Y, Hoffman K, Bhardwaj P, Piloco P, Rubio-Navarro A, Uhl S, Carrau L, Houhgton S, Redmond D, Shukla AP, Goyal P, Brown KA, tenOever BR, Alonso LC, Schwartz RE, Schenck EJ, Safford MM, Lo JC. Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2. Cell metabolism. 2021 Dec 7;33(12):2484. PMID: 34879241
  • Reiterer M, Rajan M, Gómez-Banoy N, Lau JD, Gomez-Escobar LG, Ma L, Gilani A, Alvarez-Mulett S, Sholle ET, Chandar V, Bram Y, Hoffman K, Bhardwaj P, Piloco P, Rubio-Navarro A, Uhl S, Carrau L, Houhgton S, Redmond D, Shukla AP, Goyal P, Brown KA, tenOever BR, Alonso LC, Schwartz RE, Schenck EJ, Safford MM, Lo JC. Hyperglycemia in acute COVID-19 is characterized by insulin resistance and adipose tissue infectivity by SARS-CoV-2. Cell metabolism. 2021 Nov 2;33(11):2174-2188.e5. Epub 2021 Sep 16. PMID: 34599884
  • Swain CTV, Drummond AE, Boing L, Milne RL, English DR, Brown KA, van Roekel EH, Dixon-Suen SC, Lynch MJ, Moore MM, Gaunt TR, Martin RM, Lewis SJ, Lynch BM. Linking Physical Activity to Breast Cancer via Sex Hormones, Part 1: The Effect of Physical Activity on Sex Steroid Hormones. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jan;31(1):16-27. Epub 2021 Oct 20. PMID: 34670800
  • Drummond AE, Swain CTV, Brown KA, Dixon-Suen SC, Boing L, van Roekel EH, Moore MM, Gaunt TR, Milne RL, English DR, Martin RM, Lewis SJ, Lynch BM. Linking Physical Activity to Breast Cancer via Sex Steroid Hormones, Part 2: The Effect of Sex Steroid Hormones on Breast Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jan;31(1):28-37. Epub 2021 Oct 20. PMID: 34670801
  • Lynch BM, Milne RL, English DR, Brown KA, Drummond AE, Swain CTV, van Roekel EH, Moore MM, Gaunt TR, Martin RM, Lewis SJ. Linking Physical Activity to Breast Cancer: Text Mining Results and a Protocol for Systematically Reviewing Three Potential Mechanistic Pathways. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Jan;31(1):11-15. Epub 2021 Oct 20. PMID: 34670802
  • Iyengar NM, Zhou XK, Mendieta H, El-Hely O, Giri DD, Winston L, Falcone DJ, Wang H, Meng L, Ha T, Pollak M, Morrow M, Dannenberg AJ. Effects of obesity on breast aromatase expression and systemic metabo-inflammation in women with BRCA1 or BRCA2 mutations. NPJ breast cancer. 2021 Mar 1;7(1):18. PMID: 33649363
  • Swain CTV, Drummond AE, Milne RL, English DR, Brown KA, Lou MWC, Boing L, Bageley A, Skinner TL, van Roekel EH, Moore MM, Gaunt TR, Martin RM, Lewis SJ, Lynch BM. Linking Physical Activity to Breast Cancer Risk via Inflammation, Part 1: The Effect of Physical Activity on Inflammation. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023 May 1;32(5):588-596. PMID: 36867865
  • Lou MWC, Drummond AE, Swain CTV, Milne RL, English DR, Brown KA, van Roekel EH, Skinner TL, Moore MM, Gaunt TR, Martin RM, Lewis SJ, Lynch BM. Linking Physical Activity to Breast Cancer via Inflammation, Part 2: The Effect of Inflammation on Breast Cancer Risk. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2023 May 1;32(5):597-605. PMID: 36867866
  • Rubinstein MM, Brown KA, Iyengar NM. Targeting obesity-related dysfunction in hormonally driven cancers. British journal of cancer. 2021 Aug;125(4):495-509. Epub 2021 Apr 28. PMID: 33911195
  • Brown KA, Andreopoulou E, Andreopoulou P. Endocrine Therapy-related Endocrinopathies-Biology, Prevalence and Implications for the Management of Breast Cancer. Oncology & hematology review. 2020 Spring;16(1):17-22. Epub 2020 Feb 16. PMID: 33841882
  • Zahid H, Subbaramaiah K, Iyengar NM, Zhou XK, Chen IC, Bhardwaj P, Gucalp A, Morrow M, Hudis CA, Dannenberg AJ, Brown KA. Leptin regulation of the p53-HIF1α/PKM2-aromatase axis in breast adipose stromal cells: a novel mechanism for the obesity-breast cancer link. International journal of obesity (2005). 2018 Apr;42(4):711-720. Epub 2017 Nov 6. PMID: 29104286
  • Swain CTV, Drummond AE, Milne RL, English DR, Brown KA, Chong JE, Skinner TL, van Roekel EH, Moore MM, Gaunt TR, Martin RM, Lewis SJ, Lynch BM. Linking Physical Activity to Breast Cancer Risk via Insulin/Insulin-Like Growth Factor Signaling System, Part 1: The Effect of Physical Activity on the Insulin/Insulin-Like Growth Factor Signaling System. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2022 Dec 5;31(12):2106-2115. PMID: 36464996
  • Liu S, Benito-Martin A, Pelissier Vatter FA, Hanif SZ, Liu C, Bhardwaj P, Sethupathy P, Farghli AR, Piloco P, Paik P, Mushannen M, Dong X, Otterburn DM, Cohen L, Bareja R, Krumsiek J, Cohen-Gould L, Calto S, Spector JA, Elemento O, Lyden DC, Brown KA. Breast adipose tissue-derived extracellular vesicles from obese women alter tumor cell metabolism. EMBO reports. 2023 Dec 6;24(12):e57339. Epub 2023 Nov 6. PMID: 37929643
  • Subbaramaiah K, Iyengar NM, Morrow M, Elemento O, Zhou XK, Dannenberg AJ. Prostaglandin E2 down-regulates sirtuin 1 (SIRT1), leading to elevated levels of aromatase, providing insights into the obesity-breast cancer connection. The Journal of biological chemistry. 2019 Jan 4;294(1):361-371. Epub 2018 Nov 8. PMID: 30409902
  • Wellberg EA, Kabos P, Gillen AE, Jacobsen BM, Brechbuhl HM, Johnson SJ, Rudolph MC, Edgerton SM, Thor AD, Anderson SM, Elias A, Zhou XK, Iyengar NM, Morrow M, Falcone DJ, El-Hely O, Dannenberg AJ, Sartorius CA, MacLean PS. FGFR1 underlies obesity-associated progression of estrogen receptor-positive breast cancer after estrogen deprivation. JCI insight. 2018 Jul 26;3. (14). doi: 10.1172/jci.insight.120594. eCollection 2018 Jul 26. PMID: 30046001
  • Brown KA, Scherer PE. Update on Adipose Tissue and Cancer. Endocrine reviews. 2023 Nov 9;44(6):961-974. PMID: 37260403
  • Springer NL, Iyengar NM, Bareja R, Verma A, Jochelson MS, Giri DD, Zhou XK, Elemento O, Dannenberg AJ, Fischbach C. Obesity-Associated Extracellular Matrix Remodeling Promotes a Macrophage Phenotype Similar to Tumor-Associated Macrophages. The American journal of pathology. 2019 Oct;189(10):2019-2035. Epub 2019 Jul 16. PMID: 31323189
  • Bhardwaj P, Au CC, Benito-Martin A, Ladumor H, Oshchepkova S, Moges R, Brown KA. Estrogens and breast cancer: Mechanisms involved in obesity-related development, growth and progression. The Journal of steroid biochemistry and molecular biology. 2019 May;189:161-170. Epub 2019 Mar 6. PMID: 30851382
  • Quail DF, Dannenberg AJ. The obese adipose tissue microenvironment in cancer development and progression. Nature reviews. Endocrinology. 2019 Mar;15(3):139-154. PMID: 30459447
  • Bhardwaj P, Iyengar NM, Zahid H, Carter KM, Byun DJ, Choi MH, Sun Q, Savenkov O, Louka C, Liu C, Piloco P, Acosta M, Bareja R, Elemento O, Foronda M, Dow LE, Oshchepkova S, Giri DD, Pollak M, Zhou XK, Hopkins BD, Laughney AM, Frey MK, Ellenson LH, Morrow M, Spector JA, Cantley LC, Brown KA. Obesity promotes breast epithelium DNA damage in women carrying a germline mutation in BRCA1 or BRCA2. Science translational medicine. 2023 Feb 22;15(684):eade1857. Epub 2023 Feb 22. PMID: 36812344