Table 1.

Circulating Biomarkers Proposed as Linking Adiposity with Breast Cancer Risk^{10–11, 31–32, 34–35, 37–38, 41–49}

	Biomarker	Evidence	Hypothesized Role in Cancer Risk
Insulin –Glucose and the IGF Systm	Insulin	+++	Obesity-related hyperinsulinemia is growth-promoting and antiapoptotic, inhibits hepatic secretion of SHBG and IGFBP-1, exerts mitogenic effects in breast cancer cells that may synergize with estrogen, and is associated with decreased adiponectin levels.
	Glucose	+	Growth promoter. May favor selection of malignant cell clones.
	IGF1	++	Mitogenic, antiapoptotic, proangiogenic, regulates cell size, increases cell migration, potentiates growth factors
	IGFBP-1	++	Prolonged hyperinsulinemia reduces IGFBP-1 levels, leading to increased IGF1 bioactivity
Endogenous sex hormones	Estradiol	+++	Higher levels in postmenopausal women caused by conversion of androgenic precursors through increased aromatase enzyme activity in adipose tissue. Mitogenic in normal and neoplastic mammary tissues. May be associated with increased CRP levels.
	Testosterone	++	May directly stimulate breast cell proliferation or serve as estrogen precursor.
	SHBG	++	Regulates the bioavailability of estradiol and testosterone. May have hormone independent effects on breast tissue.
	CRP	++	Marker of chronic inflammation at the vascular level associated with cancer risk. High levels of estradiol may correlate with CRP concentrations.
	TNF-α	+	Proinflammatory cytokine. The release of this protein from adipose tissue gives rise to insulin resistance.
	IL-6	+	Proinflammatory cytokine. Highly correlated with adiposity and insulin resistance. Stimulates the growth and differentiation of malignant cells. Governs CRP production.
	SAA	+	A proinflammatory and lipolytic adipokine recently associated with poor breast cancer outcomes.
	Resistin	+	May induce insulin resistance or impair hepatic sensitivity to insulin.
	Adiponectin	+	Insulin-sensitizing, anti-diabetic, anti-inflammatory, proapoptotic and antiangiogenic. Lower levels linked to increased risk of breast cancer or more aggressive phenotype.
	Leptin	+	Mediator of energy balance and immune processes. Elevated levels are observed in obese individuals, induce the growth of breast cancer cells, and can mediate angiogenesis. Associated with SHBG and insulin levels.

Epidemiologic evidence for the association of the biomarker with cancer risk:

⁺⁺⁺Supported by reviews, meta-analyses and/or clinical trials;

⁺⁺Association observed in numerous (3+) observational studies;

⁺Association observed in small number of observational studies.

Abbreviations: IGF1=insulin-like growth factor-1; IGFBP1=IGF binding protein-1; SHBG=sex hormone binding protein; CRP=C-reactive protein; TNF-α=tumor necrosis factor-alpha; IL-6=interleukin 6; SAA=serum amyloid A.