AS284 - Obesity-related Pathways and Risk of Benign Proliferative Breast Disease
This page provides study documentation for AS284. For description of the specimen results, see Specimen Results Description (open to public). Data sets of the specimen results are included in the existing WHI datasets located on the WHI Data on this site (sign in and a completed Data Distribution Agreement are required; see details on the Data site).
Investigator Names and Contact Information
Thomas Rohan [Thomas.Rohan@einstein.yu.edu]
Introduction/Intent
Benign proliferative breast disease (BPBD) is a putative breast cancer precursor and knowledge of the etiology of BPBD may enhance our understanding of the origins of breast cancer. Obesity is an established risk factor for postmenopausal breast cancer and is associated with hyperinsulinemia, increased peripheral synthesis of estrogen and elevated levels of proinflammatory cytokines. In two recently completed WHI-OS ancillary studies of breast cancer, we observed significant and independent positive associations between insulin, estradiol, C-reactive protein (an inflammatory marker) and incident breast cancer, while adiponectin, an adipocyte-derived protein with insulin-sensitizing and anti-proliferative properties, was inversely associated with breast cancer risk. Given that BPBD is characterized by epithelial proliferation, and that each of the aforementioned obesity-related molecular pathways can lead to proliferation of breast tissue, we hypothesize that hyperinsulinemia, estrogen and inflammation might be etiologically relevant to BPBD. To test this hypothesis, we propose to prospectively investigate the associations of insulin, estradiol, C-reactive protein and adiponectin with the incidence of BPBD. Specifically, using incident cases of BPBD identified in the completed Benign Breast Disease ancillary study (AS-130), we propose to conduct a nested case-control investigation involving 700 cases of BPBD (297 with atypical hyperplasia and 403 without atypia) and 1,400 matched controls (women free of any benign breast disease).
Specific Aims
Benign proliferative breast disease (BPBD) is a putative breast cancer precursor. A history of BPBD is known to be associated with a two to five-fold increased risk of developing breast cancer; however, the etiology of BPBD is poorly understood. A greater understanding of the molecular pathways that play a role in the development of BPBD could enhance our understanding of the origins of breast cancer and maybe help identify women who would benefit from increased surveillance and screening. Among postmenopausal women, obesity is an established, positive risk factor for breast cancer and there are also limited data to suggest that obesity may increase risk of BPBD. The positive association between obesity and breast cancer has been explained, in part, by the increased synthesis of peripheral estrogens in adipose tissue. However, obesity is associated with a number of other endocrinologic and physiologic abnormalities that may also play a role in breast cancer development.
Hyperinsulinemia is also common in obese individuals, and recent data from our research group suggest that insulin – which has mitogenic and anti-apoptotic activity in addition to its metabolic effects – may play a significant role in breast carcinogenesis independent of estrogen. In brief, we prospectively studied the associations of incident breast cancer with fasting serum insulin, insulin-like growth factor-I and estradiol in the WHI OS. In total, 835 incident breast cancer cases, and a random subcohort of 810 WHI women were assessed. Among women not using hormone therapy, the risk of breast cancer was independently associated with insulin (hazard ratio comparing highest to lowest quartile [HRq4-q1] = 2.40; 95% CI, 1.30 - 4.41) and estradiol (HR for highest versus lowest tertile=1.87; 95% CI, 1.11-3.15). Further, the observed positive association of obesity with breast cancer was markedly attenuated following adjustment for insulin level, suggesting hyperinsulinemia plays a substantial role in the obesity-breast cancer relationship.
Obesity is also associated with the increased secretion of adipocytokines and inflammatory markers from adipose tissue. Obese individuals have been shown consistently to have high circulating concentrations of C-reactive protein, interleukin-6 and leptin, and low levels of adiponectin. Inflammation has been linked to the initiation and progression of breast carcinogenesis and several adipocytokines have been demonstrated to exhibit pro- or anti-proliferative activity. We recently conducted a prospective evaluation of adipocytokines and inflammatory markers and risk of breast cancer among women enrolled in the WHI-OS ancillary study described above. Levels of adiponectin, an adipocytokine that has anti-proliferative effects on breast cells, were inversely associated with breast cancer incidence (hazard ratio for highest vs lowest quartile of adiponectin level = 0.68, 95% confidence interval [CI] = 0.49 – 0.96, Ptrend = .07), while among non-HT users, C-reactive protein levels were positively, albeit non-linearly, associated with breast cancer risk in a multivariable model that controlled for established breast cancer risk factors, in addition to insulin and estradiol levels (HR for combined 3rd and 4th vs lowest quartile (HRq3+4-q1) of CRP level = 1.70, 95% CI = 1.22-2.39).
Given that the hallmark of BPBD is epithelial proliferation, and that a common characteristic of each of the aforementioned obesity-related pathways is pro-proliferative activity, we hypothesize that hyperinsulinemia, estrogen and inflammation might be etiologically relevant to BPBD. To test this hypothesis, we propose to prospectively investigate the independent associations of fasting insulin, estradiol, C-reactive protein and adiponectin (the four factors that were independently associated with breast cancer in our previous ancillary studies) with the incidence of BPBD. Specifically, using incident cases of BPBD identified in the completed Benign Breast Disease (BBD) ancillary study in the WHI Clinical Trial (AS 130), we will conduct a nested case-control study involving 700 cases of BPBD (297 with atypia and 403 without atypia) and 1,400 matched controls (women free of any benign breast disease).
Our Specific Aims are:
1.To investigate the independent associations of baseline fasting insulin, estradiol, C-reactive protein and adiponectin, with risk of benign proliferative breast disease among women enrolled in the WHI Clinical Trial.
2.To evaluate whether the associations of insulin, estradiol, C-reactive protein and adiponectin with BPBD differ according to the presence or absence of atypia.
Exploratory Aim:
3.To investigate whether insulin, estradiol, C-reactive protein and adiponectin are associated with progression of BPBD to breast cancer.