W7L2 Tues breast development Flashcards
breast development in early foetal
4 weeks: pair of mammary lines develop + form mammary ridge where mammary epithelium + nipples form
§ Mammary lines separate + form placodes which induce invasion + formation of mammary sprout which induces formation of the early fat pad → mammary sprouts then branch
§ Rodent males do not have nipples: androgen receptor expression in underlying inductive mesenchyme induces expression of target gene (tenascin) which inhibit mammary gland epithelium growth + induce apoptosis = regression of mammary epithelium; AR expression absent in females
§ Humans: no sexually dimorphic signal present at this time point to induce regression of mammary epithelium
Foetal breast development
§ Week 5 (mammary rudiment induction)
→ week 6 (enlarging of rudiment)
→ week 8 (formation of branches connected to central stem)
→ week 14 (elongation of ducts)
→ week 30 (initiation of terminal ends of ducts)
→ week 34 (terminal ends)
post natal breast development
At birth: branches but not much invasion, thickened ends
pubertal breast development
- Influence of oestrogen: deposition of fat + stromal tissue in breast; invasion of mammary epithelium at terminal ends
§ Significant increase in contribution of immune cells
Adult breast structure
- Breast consists mainly of ducts with small lumen
- No glands (alveoli) in general
- Loose connective tissue surrounds ducts that makes up the majority of breast tissue
breast development in pregnancy
§ Full gland (alveoli) + duct development completed by end of 6th month of gestation, but not functional
§ Before pregnancy: mammary gland is active (turns over) in response to cyclical fluctuations in hormones
§ During pregnancy, high proliferation then differentiation of epithelial cells, and decrease in connective & adipose tissues
§ Lactating stage: acini expand + milk is released into lumen
§ A full term pregnancy induces permanent change in breast epithelium
Species breast variation : rabbit and cow
- Rabbit: central nipple structure with galactophore branching in all directions
- Cow: large cistern (high water content + volume of milk production) + galactophores
species breast variation: mouse
fat pad which mammary epithelium invades
§ Puberty: terminal end buds (TEB) that invade
§ Nulliparous adult: mammary fat pad completely filled by sparse branching mammary epithelium
§ Pregnancy: formation of alveolar buds
§ Lactation: fat + stroma completely replaced by milk producing epithelium (mature alveoli)
* Mammary epithelium: myoepithelial cells/basal cells + luminal cells on inside (milk producing
breast structure
- Normal breast epithelium composed of ducts (transport) and lobules (milk production) composed of two lineages
- Basal (contractile/invasive - expel milk/initiate invasion)
- Luminal alveolar (produce milk)
- Luminal are hormone-sensing (respond to hormonal cues + translate cues into paracrine signals sent to alveolar cells + basal cells to coordinate development + pregnancy associated development)
Hormone role in breast development
- Normal breast development and function is largely controlled by endocrine reproductive steroids (estrogen & progesterone)
- Estrogen promotes breast growth, progesterone promotes preparation for lactation
- Androgens inhibit estrogen-induced breast growth
- Actions of all three heavily integrated (biosynthetic and genetic)
- ER required for PR expression/action
Steroid Signalling + Interactions
-oestrogen enter directly the plasma membrane, bind to ER
-ER oestrogen complex bind to oestrogen response element in the DNA, after entering the nucleus
-lead to transcription activation
Ø Every sex steroid receptor has its individual response element
Role of co-factor
§ Cofactors bind to sex steroid receptors in nucleus + can influence effect of receptor (inhibit/activate) +ability of receptor binding to a gene, if at all
Ø FOXA1: allows oestrogen receptor to bind + initiate breast growth
Ø Co-activators can induce an increase in transcription
Ø Co-repressors bind AR + ER, blocking transcription
Ø Co-repressor induction: AR induces expression of genes that bind ER + act as a co-repressor
Ø Direct competition: AR displaces ER from DNA binding
Ø Interference with co-activators: sequester factors required by ER for binding
Cofactor in steroid signaling RIME
§ RIME: E2 treated breast cells + E2/P4 treated breast cells
→ crosslink + fragment DNA
→ immunoprecipitated ER + PR
→ wash
→ detect cofactors
§ PR reprogrammes ER genome binding (breast cancer):
PR reprogrammes ER genome binding (breast cancer):
Ø ER (+cofactors) bind to ERE initiate proliferation + pro-survival
Ø PR therapy: PR displaces ER + binds to PRE = initiates differentiation + cell death
§ Biosynthesis: 1 gene CYP19A1 responsible for encoding aromatase (converts testosterone to oestradiol)
