Breast remodelling

Question 1

What are the milk producing units of the mammary gland?

Answer 1

Luminal epithelium of the mammary gland alveoli

Question 2

Describe the structure of the mammary tree

Answer 2

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

Question 3

What is the importance of apico-basal polarity within the mammary gland?

Answer 3

Ensures it direct milk secretion towards the lumen

Question 4

What is the main transmembrane receptor through which cell adhesion to the ECM occurs?

Answer 4

Integrin

Question 5

What would be observed if B1 integrin is deleted in mammary gland or luminal epithelium?

Answer 5

Lumen filling defect

Question 6

Which adhesome component downstream of integrin controls lumen formation?

Answer 6

Ilk

NOT FAK

Question 7

How is the luminal epithelium membrane remodelled?

Answer 7

1. Initially, cells are unpolarised
2. Integrin interacts with basement membrane
3. Integrin recruits Ilk, forming an integrin/Ilk complex
4. Integrin/Ilk complex interact with the plus ends of microtubules to polarise them
5. This induces endocytosis of apical components from the basolateral membrane
6. Integrin/Ilk also position the Golgi sub-apically to aid trafficking of apical components to the apical membrane

Question 8

How is B1 integrin involved in mammary gland alveoli development by cell proliferation?

Answer 8

1. Growth factors cause phosphorylation of Erk
2. Matrix signals through
   B1 integrin
3. B1 integrin interacts with talin and FAK
4. Talin and FAK causes phosphorylated Erk to translocate into the nucleus and drive the cell cycle program

Question 9

Which hormone is involved in milk production and how does it work?

Answer 9

• 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.

Question 10

In adhesion signalling in mammary epithelial cell lactational differentiation, what does Ilk signal through?

Answer 10

Parvin –> alpha pix

Question 11

Which Rho family GTPase is needed for full lactation?

Answer 11

Rac1

Question 12

What triggers mammary gland involution?

Answer 12

• Weaning of infant

Question 13

Describe phase 1 of involution

Answer 13

• Reversible
• 48 hours
• epithelial cell death and de-differentiation of alveoli –> milk production stops

Question 14

How does a Rac1 KO affect involution?

Answer 14

• 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