Breast development
Breast development, also known as mammogenesis, is a complex biological process in primates that takes place throughout a female's life.
[9] GH induction of IGF-1 production and secretion occurs in almost all types of tissue in the body, but especially in the liver, which is the source of approximately 80% of circulating IGF-1,[10] as well as locally in the breasts.
[8][9][14] 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.
[15][16] An animal model of Laron syndrome, the GHR knockout mouse, shows severely impaired ductal outgrowth at 11 weeks of age.
[17][19] 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.
[20] During puberty in females, estrogen, in conjunction with GH/IGF-1, through activation of ERα specifically (and notably not ERβ or GPER),[23][24] causes growth of and transformation of the tubules into the matured ductal system of the breasts.
[20][21][25] This continues until a tree-like network of branched ducts that is embedded into and fills the entire fat pad of the breast is formed.
[27] In addition, progesterone produces modest lobuloalveolar development (alveolar bud formation or ductal sidebranching) starting at puberty,[20][25] specifically through activation of PRB (and notably not PRA),[28] with growth and regression of the alveoli occurring to some degree with each menstrual cycle.
[28] In contrast to the case of the PR, ER expression in the breast is stable and differs relatively little in the contexts of reproductive status, stage of the menstrual cycle, or exogenous hormonal therapy.
[39][40] Growth hormone receptor (GHR) knockout mice also show greatly impaired lobuloalveolar development.
[41] In addition to their role in lobuloalveolar growth, prolactin and hPL act to increase the size of the nipple-areolar complex during pregnancy.
[42] By the end of the fourth month of pregnancy, at which time lobuloalveolar maturation is complete, the breasts are fully prepared for lactation and breastfeeding.
[54] Conversely however, it has been found that VDR knockout mice show reduced ductal differentiation, represented by an increased number of undifferentiated TEBs,[56] and this finding has been interpreted as indicating that vitamin D may be essential for lobuloalveolar development.
[40] These factors regulate cellular growth, proliferation, and differentiation via activation of intracellular signaling cascades that control cell function, such as Erk, Akt, JNK, and Jak/Stat.
[74] Also in accordance, treatment of mice with amphiregulin or other EGFR ligands like TGF-α or heregulin induces ductal and lobuloalveolar development in the mouse mammary gland, actions that occur even in the absence of estrogen and progesterone.
[69][76] As both the IGF-1R and the EGFR are independently essential for mammary gland development, and as combined application of IGF-1 and EGF, through their respective receptors, has been found to synergistically stimulate the growth of human breast epithelial cells, these growth factor systems appear to work together in mediating breast development.
[20][21][29] Prolactin suppresses the secretion of LH and FSH, which in turn results in continued low levels of estrogen and progesterone, and temporary amenorrhea (absence of menstrual cycles) occurs.
[82] Some of these include rs7816345 near ZNF703 (zinc finger protein 703); rs4849887 and rs17625845 flanking INHBB (inhibin βB); rs12173570 near ESR1 (ERα); rs7089814 in ZNF365 (zinc finger protein 365); rs12371778 near PTHLH (parathyroid hormone-like hormone); rs62314947 near AREG (amphiregulin);[82] as well as rs10086016 at 8p11.23 (which is in complete linkage disequilibrium with rs7816345) and rs5995871 at 22q13 (contains the MKL1 gene, which has been found to modulate the transcriptional activity of ERα).
[85] 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.
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.
