Table 1.

Possible mechanisms relating commonly proposed biomarkers to postmenopausal breast cancer risk and physical activity

Proposed biomarkerPossible role in postmenopausal breast cancerPossible impact of physical activity in postmenopausal women
EstrogensAdipose tissue contains higher levels of aromatase which converts androgens to estrogens (57).Reduces adiposity thereby lowering the capacity for conversion of androgens to estrogens by aromatase and lowering circulating estrogen levels (10, 221).
Estrogens are mitogens in the breast, stimulating mammary cell proliferation through estrogen receptor–mediated transcriptional activity and by activation of intracellular signaling pathways (48, 57).Reduces insulin levels thereby increasing SHBG levels (73-75) which may decrease estradiol bioavailability.
AndrogensTestosterone and androstenedione may increase risk upon conversion to estradiol and estrone, respectively, in adipose tissue (58, 222).Decreases testosterone levels through loss of body fat. Decreased adiposity lowers levels of 17β-hydroxysteroid dehydrogenase enzyme which converts androstenedione to testosterone in s.c. and intra-abdominal fat (228), thereby lowering testosterone levels.
Androgens also act directly on breast cells by binding to the androgen receptor (65), a ligand-dependent transcription factor expressed in the majority of breast cancers (223, 224).Reduces adiposity thereby lowering the capacity for conversion of androgens to estrogens by aromatase and lowering circulating estrogen levels (10, 221).
There may be synergy between estrogens and androgens in increasing breast cancer risk (69).Reduces insulin levels thereby increasing SHBG levels (73-75) which may decrease testosterone bioavailability.
The exact mechanism in postmenopausal breast cancer is unclear (69, 225). In vitro, androgens can directly stimulate or inhibit breast cancer cell proliferation depending on the cell line (69, 226, 227). Some clinical data support a protective role for androgens in breast cancer (227).
SHBGSHBG binds to estradiol and testosterone (55) thereby reducing their bioavailabilities; may act as a negative modulator of estradiol (54).Reduces insulin levels which increases circulating SHBG (73, 229), thereby decreasing the bioavailabilities of estradiol and testosterone.
Insulin ResistanceHyperinsulinemia is associated with decreased plasma SHBG (73, 229), thereby increasing sex hormone bioavailability.An acute bout of exercise enhances insulin sensitivity and glucose uptake mainly on account of skeletal muscle activity; however, the effects tend to dissipate within days (78).
Insulin exerts mitogenic effects in breast cancer cells in vitro; (230, 231) may synergize with estrogen (57, 232).Prolonged high intensity exercise training can sustain insulin sensitivity (76, 78) and protect against development of type 2 diabetes (77) perhaps by reducing abdominal fat, increasing skeletal muscle mass, increasing glucose transport into the muscle,(235) or decreasing fatty acid synthesis (76, 78).
Insulin resistance and hyperinsulinemia are strongly related to obesity,(233) and particularly intra-abdominal fat (73, 234). Insulin resistance has been associated with increased leptin, TNF-α, adipose tissue–derived IL-6, and decreased adiponectin, respectively (15, 117).
Body weight, BMIOverweight and obesity generally results in: higher levels of sex hormones (71, 236, 237);Reduces body weight (41) and decreases central adiposity in some populations (239) including postmenopausal women (17, 107, 108, 216, 240).
higher levels of aromatase, which converts androgens to estrogens in adipose tissue, and therefore higher levels of total estradiol (57, 75, 238);
more abdominal fat and thus more 17β-hydroxysteroid dehydrogenase, which regulates the conversion of androstenedione to testosterone (228);
chronic release of free fatty acids from adipose tissue, resulting in reduced uptake of glucose by the tissues and consequently, increased circulating insulin (57, 238);
lower levels of SHBG in response to hyperinsulinemia and thus, higher circulating levels of bioavailable estradiol and testosterone (57, 238);
greater release of leptin, IL-6, and TNF-α from adipose tissue and decreased adiponectin (57, 111, 141, 238).