However, conversely, some polymorphisms show a negative association between breast size and breast cancer risk. In any case, a meta-analysis concluded that breast size and risk of breast cancer are indeed importantly related.Circulating IGF-1 levels are positively associated with breast volume in women. In addition, the absence of the common 19-repeat allele in the IGF1 gene is also positively associated with breast volume in women, as well as with high IGF-1 levels during oral contraceptive use and with lessening of the normal age-associated decline in circulating IGF-1 concentrations in women. There is great variation in the prevalence of the IGF1 19-repeat allele between ethnic groups, and its absence has been reported to be highest among African-American women.Genetic variations in the androgen receptor (AR) have been linked to both breast volume (as well as body mass index) and breast cancer aggressiveness.COX-2 expression has been positively associated with breast volume and inflammation in breast tissue, as well as with breast cancer risk and prognosis. Rare mutations
Women with CAIS, who are completely insensitive to the AR-mediated actions of androgens, have, as a group, above-average sized breasts. This is true despite the fact that they simultaneously have relatively low levels of estrogen, which demonstrates the powerful suppressant effect of androgens on estrogen-mediated breast development.Aromatase excess syndrome, an extremely rare condition characterized by marked hyperestrogenism, is associated with precocious breast development and macromastia in females and similarly precocious gynecomastia (womens breasts) in males.
In addition to estrogen and GH/IGF-1 both being essential for pubertal breast development, they are synergistic in bringing it about.Despite the apparent necessity of GH/IGF-1 signaling in pubertal breast development however, women with Laron syndrome, in whom the growth hormone receptor (GHR) is defective and insensitive to GH and serum IGF-1 levels are very low, puberty, including breast development, is delayed, although full sexual maturity is always eventually reached. Moreover, breast development and size are normal (albeit delayed) in spite of GH/IGF-1 axis insufficiency, and in some the breasts may actually be large in relation to body size. The relatively large breasts in women with Laron syndrome have been suggested to be due to increased secretion of prolactin (which is known to produce breast enlargement) caused by a drift phenomenon from somatomammotrophic cells in the pituitary gland with a high GH secretion. An animal model of Laron syndrome, the GHR knockout mouse, shows severely impaired ductal outgrowth at 11 weeks of age. However, by 15 weeks, ductal development has caught up with that of normal mice and the ducts have fully distributed throughout the mammary fat pad, although the ducts remain narrower than those of wild-type mice. In any case, female GHR knockout mice can lactate normally. As such, it has been said that the phenotypes of women with Laron syndrome and GHR knockout mice are identical, with diminished body size and delayed sexual maturation accompanied by normal lactation.