[This page is intended to provide a study summary, the sections of which are below. Please complete these sections, as applicable. The headings below are suggested headings. You can remove inapplicable sections, or add new ones relevant to your study]
Investigator Names and Contact Information
Su Yon Jung (firstname.lastname@example.org)
Postmenopausal women have an increased risk of developing breast cancer and colorectal
cancer (CRC). The majority of new breast cancer and CRC cases (80% and 90%, respectively)
occur in women age 50 years and older,
and obesity is a well-established risk factor.
Insulinlike growth factors (IGFs)/insulin resistance (IR) axis has been considered one of the major
hormonal pathways mediating the biologic mechanism between obesity and postmenopausal
breast cancer and CRC development.
IGFs/IR axis is central in developing many obesityrelevant cancers, including postmenopausal breast cancer and CRC,5-10 by overexpressing insulin
and insulin-like growth factor receptors, leading to hyperactive and abnormal multiple cellular
signaling downstream cascades, which are necessary in the tumor growth and development
environment in particular cells.
5,11-13 IGFs/IR axis therefore may be associated with carcinogenesis.
Chronic inflammation also plays an important role in the pathogenesis of colorectal cancer
and as reported in more recent research, breast cancer, in postmenopausal women from tumor
initiation to progression.14-16 The key inflammatory cytokines such as C-reactive protein (CRP)
and interleukin-6 (IL-6) reflect different molecular pathways in the immune cascade in acute and
chronic immune responses but may be interrelated in carcinogenesis.15
The systemic development of metabolic (IGFs and IR) and inflammatory cytokines (CRP
and IL-6) can be influenced by not only environmental4,17,18 but also genetic and epigenetic
19 Despite advances in the understanding of genetic variances and gene–environment
interactions in relation to those cytokines, common genetic variants explain a small proportion of
the variation (IGFs/IR and CRP, < 5% each; IL-6, < 2%).
20-24 The analysis of epigenetics may, we
hope, clarify some of the variation and provide insights into the mechanisms related to the
biomarkers at the molecular level. DNA methylation (DNAm) is the well-characterized epigenetic
modification. It involves mitotically heritable and reversible attachment of methyl groups at the 5´
carbon of cytosine in CpG dinucleotides, influencing DNA transcription without altering the
primary DNA sequence.
25-27 DNAm is modifiable via lifestyle and environmental factors such as
30 and environmental pollutants.
31 Finally, DNAm reflects a wide
range of environmental exposures and genetic influences, regulating gene expression, and
potentially affecting the risk for disease.
Thus, the differential DNAm pattern in those metabolic and inflammatory cytokines may
encompass interactions with lifestyles and serve as a useful biomarker for the susceptibility to
breast cancer and CRC.34-36 Up to now, few studies17,37-42 have examined DNAm in relation to
those cytokines at the epigenome-wide level and the results are inconclusive. Notably, those
studies have neither determined the temporality of the cytokine and DNAm (i.e., which comes
first) nor incorporated clinical consequences associated with the cytokine, such as cancer. Studying
DNAm in relation to the metabolic and inflammatory cytokines that mediate risk for breast cancer
and CRC reflects a largely untapped population-based genomic science resource and is important
to understand the molecular underpinnings of those cytokines in cancer development. Further,
integrating such epigenetic markers with genetic and lifestyle factors to construct risk profiles for
breast cancer and CRC is important in developing a tool for cancer prevention and treatment
efforts, but they are rare.
43 Without such studies, resolving the conflict over breast cancer and CRC
causation and providing a plausible biologic basis for cancer therapies may be delayed.
Our research goal is to understand how the pathways of obesity–metabolic and
inflammatory cytokines (epigenetic/genetic)–breast cancer/CRC can be manipulated for the
purpose of prevention. Our overall hypothesis is that epigenetic modification associated with those
cytokines is a genomic pathway by which obesity factors influence the risk for breast cancer and
CRC. We propose an Ancillary Study with a nested case-control study design from the WHI
Observational Studies and Clinical Trails.