Obesity is an established risk factor for hormone receptor (HR)-positive breast cancer in post-menopausal women. This increased risk is thought to be partly attributable to increased estrogen production from adipose tissue, since adipose tissue is the primary site of action of the estrogen-synthesizing enzyme aromatase post climacteric. Given the current epidemic of obesity, there is a pressing need to develop mechanism-based strategies to reduce the cancer risk among this sector of the population. Estrogen deprivation is a commonly used approach for breast cancer prevention and treatment, but both SERMs and aromatase inhibitors have significant side effects that restrict their widespread use for prophylaxis. We hypothesize that by targeting the pathways that drive increased aromatase expression it will be possible to suppress estrogen overproduction in adipose tissues, including the breast, and hence reduce the risk of HR-positive breast cancer in the overweight and obese. Importantly in this respect, a key role has been established for cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) in stimulating transcription of the CYP19 gene which encodes the aromatase enzyme. We have reported that COX-2 overexpression in the mammary gland (MG) leads to increased PGE2 production and elevated aromatase expression. Strikingly, we have now found that significant inflammation, elevated COX-2 expression and increased aromatase levels occur in both the MG and visceral fat (VF) in mouse models of obesity. These exciting findings raise the very real possibility that obesity-related inflammatory changes in both the MG and VF contribute to elevated aromatase activity and thereby an increased risk of HR- positive breast cancer. Therefore, the goal of this proposal is to evaluate strategies for disrupting arachidonic acid metabolism and thereby suppressing the PGE2->aromatase axis, with the ultimate goal of "normalizing" the increased levels of aromatase associated with obesity. In SA1, we will define the interrelationships between PGE2, BRCA1, histone acetylation and aromatase induction, based on our novel data implicating BRCA1, Sirt-1 and CBP/p300 in PGE2-mediated aromatase induction. In SA2, we will evaluate whether COX- 1, mPGES-1 or 15-PGDH, enzymes involved in the synthesis or catabolism of PGE2, are determinants of aromatase expression and activity in the MG and VF using knockout mouse strains. In SA3, we will explore the mechanism(s) by which n-3 fatty acids modulate the PGE2->aromatase pathway, since n-3 fatty acids have been shown to suppress PGE2 synthesis and protect against experimental breast cancer. Finally, in SA4 we will test whether n-3 fatty acids, alone or combined with a COX-2 inhibitor, suppress inflammation and reduce aromatase levels in vivo in the MG and VF of obese mice. If either a pharmacological or dietary approach disrupts the obesity->inflammation->COX->aromatase pathway, this would represent a significant advance and strengthen the rationale for addressing similar questions in women. Collectively, the results of the proposed studies will offer new insights into strategies to reduce the risk of HR-positive breast cancer.
We have shown that obesity drives an inflammatory process in adipose tissue leading to increased expression of the estrogen synthesizing enzyme aromatase. Here we propose to test if either a pharmacological or dietary approach, or the combination thereof, disrupts the obesity->inflammation->cyclooxygenase->aromatase pathway. Positive findings in this study would provide a platform for evaluating new strategies for reducing hormone receptor-positive breast cancer.
|Mohanan, Sunish; Horibata, Sachi; McElwee, John L et al. (2013) Identification of macrophage extracellular trap-like structures in mammary gland adipose tissue: a preliminary study. Front Immunol 4:67|
|Howe, Louise R; Subbaramaiah, Kotha; Hudis, Clifford A et al. (2013) Molecular pathways: adipose inflammation as a mediator of obesity-associated cancer. Clin Cancer Res 19:6074-83|
|Subbaramaiah, Kotha; Sue, Erika; Bhardwaj, Priya et al. (2013) Dietary polyphenols suppress elevated levels of proinflammatory mediators and aromatase in the mammary gland of obese mice. Cancer Prev Res (Phila) 6:886-97|
|Iyengar, Neil M; Hudis, Clifford A; Dannenberg, Andrew J (2013) Obesity and inflammation: new insights into breast cancer development and progression. Am Soc Clin Oncol Educ Book :46-51|
|Howe, Louise R; Subbaramaiah, Kotha; Kent, Claire V et al. (2013) Genetic deletion of microsomal prostaglandin E synthase-1 suppresses mouse mammary tumor growth and angiogenesis. Prostaglandins Other Lipid Mediat 106:99-105|
|Bhardwaj, Priya; Du, Baoheng; Zhou, Xi Kathy et al. (2013) Caloric restriction reverses obesity-induced mammary gland inflammation in mice. Cancer Prev Res (Phila) 6:282-9|