DSF - 1-12-12 - Physiology - Breast, Lactation, and Breast Cancer

Estradiol

Growth hormone

Serum estradiol and progesterone bind to breast epithelial cells with estrogen and progesterone receptors (~10%-20% of all breast epithelial cells)

Hormone action triggers release of growth factors that act on adjacent cells to promote proliferation

Prolactin secretion is under tonic inhibition by tuberoinfundibular dopaminergic neurons of the hypothalamus

Suckling:
- Inhibits tuberoinfundibular dopaminergic neurons of the hypothalamus

Estradiol:
- Increases prolactin gene expression
- Increases number of lactotrophs
- Inhibits tuberoinfundibular dopaminergic neurons of the hypothalamus

TRH

VIP

Prolactin secretion:
- Short loop negative feedback increases dopamine secretion from tuberoifundibular dopaminergic neurons of the hypothalamus

Increase prolactin secretion

Gynecomastia (breast enlargement)

Galactorrhea (inappropriate milk secretion)

Oxytocin binds to myoepithelial cells and promotes milk let down

1. Suckling, neural, and sensory cues stimulates sensory terminals and is transmitted to the hypothalamus

2. Increased firing of oxytocinergic neurons in paraventricular nucleus and preoptic nucleus of the hypothalamus

3. Oxytocin released from posterior pituitary and into circulation

Stimulates milk production

Only oxytocin triggers milk letdown

Only suckling stimulates prolactin secretion

Synergize with prolactin and control milk protein production

Promote synthesis of prolactin

1. Binds prolactin receptor

2. Receptor dimerizes

3. Second messengers change gene expression

4. Milk constituents produced:
- Casein
- Sugar production enzymes
- Lactalbumin
- Lipoprotein lipase

1. Oxytocin binds plasma receptors on myoepithelial breast cells

2. Phospholipase C activated and downstream activation of IP3 and DAG

3. Intracellular calcium rises

4. Myoepithelial contraction triggers milk letdown by increasing positive pressure in the alveoli, forcing milk into the ducts

- Milk proteins
- Calcium
- Lactose
- Citrate


Exocytosis into milk via Golgi-derived secretory vesicles

1. PTH-RP made by breast cells frees calcium from bone into circulation

2. Calcium receptors on breast cells sense calcium levels

3. Calcium pumped from cytoplasm into Golgi

1. Lipid droplets made by mammary cells are engulfed by breast epithelial cells

2. Droplets bulge and separate from the cells a the milk fat globule

3. Milk fat globule is released into the alveolar lumen during the latter part of feeding

Water:
- Water is driven from the epithelial cell into milk via osmotic gradient caused mainly by lactose in the milk

Sodium:
- Sodium is reabosrbed into breast cells driven by actions of prolactin and mineralocorticoids

1. Secretory immunoglobulins are made by B lymphocytes and plasma cells

2. Immunoglobulins are secreted into capillaries around myoepithelial cells

3. Alveolar cells take up IgGs by pinocytosis

4. IgGs secreted into breast milk via exocytosis

IgA

Paracellularly by transversing tight junctions between alveolar cells

Well, rabbi. Well.

Baby's GI physiology permits survival of hormones, growth factors, proteins, and cells

Fore milk (secreted early in feed):
- High volume
- Rich in lactose

Hind milk (secreted late in feed):
- High in fat

Natural contraceptive

Breast cancer reduction

Ovarian cancer reduction

Pregnancy differentiates the breast more completely

Lower ovarian steroid exposure

Reduced ovulation and minor monthly ovarian trauma that comes with it

1. Suckling and elevated prolactin suppress GnRH pulsatile release

2. Suppressed FSH and LH secretion

3. Suppressed ovarian follicular growth

Spontaneous discharge of milk in the absence of pregnancy

Abnormally high prolactin levels

Caused by decreased GnRH secretion
Also secondary to hypothyroidism (Increased TRH)

Symptoms include amenorrhea and increased chances of pregnancy and lactation

Treated by administration of dopamine receptor agonists or surgery in the case of pituitary tumors

If there are estrogen receptors on breast cancer cells, estrogen receptor antagonists can be used to treat breast cancer with a relatively good prognosis

Examples: Tamoxifen, Raloxifene (estrogen receptor antagonists)

Normal cells:
- Paracrine induction of cell proliferation
- Adjacent cells bind estrogen and progesterone and secrete growth factors that stimulate the adjacent cell to divide

Cancerous cells:
- Autocrine regulated growth of cancer cells
- Cancer cells bind estrogen and progesterone which stimulates direct cell growth after the secretion of growth factors

Inhibit or mimic estrogen-induced gene expression in some estrogen sensitive tissues

(Ex. Antagonistic effects in breast cancer cells, agonistic effects in bone)

Hot flashes

Endometrial cancer

Increased risk of stroke, PE, thrombosis

Human epidermal growth factor receptor 2

Found on many breast cancers in over abundance and respond to epidermal growth factor (EGF)

Herceptin

Monoclonal antibody that binds to HER2 receptors, inhibiting their responses to EGF

Inhibiting or inactivating aromatase

Prevents androgens, synthesized by the ovaries or adrenals, from being converted to estradiol and acting on breast cancer cells

Highly penetrant autosomal dominant breast cancer genes