What are the milk producing units of the mammary gland?
Luminal epithelium of the mammary gland alveoli
Describe the structure of the mammary tree
Ducts connected to alveoli
Ducts and alveoli are lined by luminal epithelium
Myoepithelial cell layer surrounds luminal epithelium
Laminin ECM and interstitial stromal collagen matrix surrounds structure
Entire structure is embedded in adipocyte fat pad
What is the importance of apico-basal polarity within the mammary gland?
Ensures it direct milk secretion towards the lumen
What is the main transmembrane receptor through which cell adhesion to the ECM occurs?
Integrin
What would be observed if B1 integrin is deleted in mammary gland or luminal epithelium?
Lumen filling defect
Which adhesome component downstream of integrin controls lumen formation?
Ilk
NOT FAK
How is the luminal epithelium membrane remodelled?
- Initially, cells are unpolarised
- Integrin interacts with basement membrane
- Integrin recruits Ilk, forming an integrin/Ilk complex
- Integrin/Ilk complex interact with the plus ends of microtubules to polarise them
- This induces endocytosis of apical components from the basolateral membrane
- Integrin/Ilk also position the Golgi sub-apically to aid trafficking of apical components to the apical membrane
How is B1 integrin involved in mammary gland alveoli development by cell proliferation?
- Growth factors cause phosphorylation of Erk
- Matrix signals through
B1 integrin - B1 integrin interacts with talin and FAK
- Talin and FAK causes phosphorylated Erk to translocate into the nucleus and drive the cell cycle program
Which hormone is involved in milk production and how does it work?
- Prolactin binds to prolactin receptor
- Activates Stat5/Jak2 signalling cascade
- Stat5 translocates into nucleus and drives transcription of B-casein
This also requires signals from laminin.
In adhesion signalling in mammary epithelial cell lactational differentiation, what does Ilk signal through?
Parvin –> alpha pix
Which Rho family GTPase is needed for full lactation?
Rac1
What triggers mammary gland involution?
- Weaning of infant
Describe phase 1 of involution
- Reversible
- 48 hours
- epithelial cell death and de-differentiation of alveoli –> milk production stops
How does a Rac1 KO affect involution?
- Failure of luminal epithelial cells to engulf dead cells
- Failure of luminal epithelial cells to send out macropinosomes to engulf old milk
- Early and heightened inflammatory response mediated by macrophages. However, macrophages cannot engulf milk.
- Ductal bloating phenotype because of old milk and dead cells in the lumen
- Defective remodelling means mammary gland fails to regenerate into milk producing organ in 2nd pregnancy
