12. Cancer as a Disease - Breast Cancer

Question 1

Describe the development of th breast.

Answer 1

• This is the only organ that develops after birth
• During puberty, the breast develops into a fatty glandular structure in response to hormonal cues
• There is a tubular network (embedded In a fatty stromal tissue) within the breast that comes together at the nipple
• Every part of the gland, anatomically and cellularly, can have some type of cancer
• E.g. phyllodes tumour - this is in the fatty stromal area - it is a very rare and very aggressive type of tumour
• The majority of breast cancer (>90%) originates in the luminal epithelium

Question 2

Describe the cellular organisation of the mammary gland.

Answer 2

• Between the tubules you have fatty stromal cells
• There are TWO layers of epithelial cells:
  
  • Luminal epithelial cells
  • Myoepithelial cells (surrounding the luminal cells)
• Myoepithelial cells have a contractile phenotype and they will contract when they receive the correct hormonal signals
• Myoepithelial cells are very important in the development of the gland - they are responsible for the formation of tubules (the luminal cells lie passively underneath) - important for transport of milk to nipple
• Oestrogen receptors are ONLY expressed by luminal epithelial cells but not all luminal epithelial cells express oestrogen receptors (only about 10-15%)
• In a normal gland, the response to oestrogen is to stimulate growth
• The cells that are oestrogen receptor positive do NOT grow in response to oestrogen - they acts as beacons to produce growth factors that stimulate the growth of nearby cells
• In breast cancer we see the REVERSAL of this effect - the oestrogen responsive cells directly respond to oestrogen as a growth factor and stimulates their own growth

Question 3

Describe the progression from a normal to malignant breast.

Answer 3

• Starts as a Benign/carcinoma in situ - there is proliferation of the luminal cells but the myoepithelium is still around it - this is a possible precancerous state
• Lobular Carcinoma: the tumour has some resemblance of the architecture of the gland - there are tubules of some form
• Medullary Carcinoma: the tumour cells don’t look anything like the epithelial cells from the mammary gland - have neuroendocrine morpholy
• The majority of breast cancers aren’t medullary or lobular so they are just called breast carcinoma.

Question 4

What are the main histological types of invasive breast cancer?

Answer 4

• Staining the tissue samples for oestrogen receptors (ER) is a good way of classifying breast tumours as:
  
  • ER positive
  • ER negative
• It is the nuclei that are being stained in this test because ER is a transcription factor that is found in the nucleus
• Over 80% of breast cancers are ER positive
  
  • Different labs may have different cut off points for classifying a tumour as ER positive or negative
• NOTE: Breast cancer growth is oestrogen-regulated

Question 5

What are the risk factors of breast cancer?

Answer 5

LIFE TIME EXPOSURE TO OESTROGENS

• Early age of onset of menstruation
• Late age to menopause
• Age to first full-term pregnancy
• Some contraceptive pills
• Some HRTs
• Diet, physical activity, height, medication
• Obesity (BMI - second most important risk factor)

Question 6

Describe the oestrogen receptors on the breasts.

Answer 6

• ER is a cytosolic receptor - inside the cell
• Inside the cell, the ER is bound to a heatshock protein forming a dimer
• Oestrogen is very lipophilic and can pass easily through the cell membrane
• Once inside the cell, the oestrogen binds to the ER (and displaces the heatshock protein)
• 2 oestrogen receptors then come together to form a dimer, and this dimerised protein is then able to enter the nucleus (with oestrogen bound) and locate DNA sequences in the gemnome that are response elements for this transcription factor.
• Significance of dimerisation of the ER - the response elements are present in 2 halves so each half of the dimer will bind to each half of the response elements
• The most important target genes of this transcription factor:
  
  • Progesterone receptor
  • Cyclin D1
  • C-myc
  • TGF-alpha

Question 7

Describe the oestrogen receptors in breast cancer.

Answer 7

• Some breast cancers, like the normal breast, are sensitive to the effects of oestrogen
• About 1/3 of PREmenopausal women with advanced breast cancer will respond to oophorectomy (removal of both ovaries)
• Paradoxically, breast cancer in post-menopausal women responds to HIGH-dose therapy with synthetic oestrogens- it causes breast tumour regression (tumour shrunk)
  
  • Explanation: if you overstimulate this hormone system it will result in the downregulation of ER so the cells are no longer responsive to oestrogen
• ER is overexpressed in around 70% of breast cancers
• Presence of ER is indicative of a BETTER PROGNOSIS
• Oestrogen withdrawal or competition for binding to the ER using anti-oestrogens results in a response in about 70% of ER+ cancers and 5-10% of ER- cancers also respond
• An increased level of expression of ER indicates a good prognosis in FEMALE breast cancer but a WORSE PROGNOSIS in male breast cancer (very rare)

Question 8

What are the major treatment approaches for breast cancer?

Answer 8

• Surgery – mastectomy – primary therapy
• Radiation therapy – primary therapy
• Chemotherapy
• Endocrine therapy – can be used to shrink tumour for surgery to be done

Question 9

What is the best way to treat breast cancer?

Answer 9

• Endocrine therapy is the cornerstone of breast cancer treatment - it can be achieved at the following levels:
  
  • Ovarian suppression
  • Blocking oestrogen production by enzymatic inhibition
  • Inhibiting oestrogen responses
• Ovaries are the main site of production of oestrogen in pre-menopausal women
• Levels of oestrogen production depend on the stage of the menstrual cycle - it is highest at the end of the follicular stage
• Post-menopausal women make oestrogen through aromatisation of androgens in peripheral tissues

Question 10

Describe ovarian ablation.

Answer 10

• Ovarian ablation aims to eliminate this source of oestrogen and this can be carried out by:
  
  • Surgical oophorectomy
  • Ovarian irradiation
• Major problems:
  
  • Morbidity
  • Irreversibility
• To overcomes these issues, treatments to produce medical ovarian ablation have been developed
• Reversible and reliable medial ovarian ablation can be achieved using luteinising hormone releasing hormone (LHRH) agonists
• LHRH agonists bind to LHRH receptors in the pituitary leading to receptor downregulation and suppression of LH release and inhibition of ovarian function, including oestrogen production
• Examples of LHRH agonists:
  
  • Goserelin
  • Buserelin
  • Triptorelin
  • Leuprolide

Question 11

What are the targets for breast cancer treatment?

Answer 11

Sources of oestrogen: Ovaries and adrenal glands

Adrenal glands still produce androgens in post-menopausal women

We can inhibit aromatase thus preventing the conversion of androgens to oestrogens

Question 12

What is the use of Tamoxifen?

Answer 12

• Tamoxifen is an ER receptor blocker (competitive inhibitor)
• This negates the stimulatory effects of oestrogen causing the cells to be held at the G1 phase of the cell cycle
• Tamoxifen is the endocrine treatment of choice for metastatic disease in post-menopausal patients (about 1/3 of patients respond)
• Few side effects - hot flushes is the most commonly reported
• Tamoxifen is a SERM (selective oestrogen receptor modulator)
  
  • Tamoxifen is oestrogenic in bone so it can protect post menopausal women against osteoporosis
  • Tamoxifen is oestrogenic on the cardiovascular system so it can decrease atherosclerosis risk in women
• However, there has been some evidence that tamoxifen increases the risk of thromboembolic events and it can cause endometrial hyperplasia (increases risk of endometrial cancer)

Question 13

Describe the use of derivatives of tamoxifen.

Answer 13

• Toremifene is a structural derivative of tamoxifen with similar effects
• Faslodex shows no oestrogen like activity in laboratory tests, but it is effective in controlling oestrogen-stimulated growth
  
  • Faslodex is a pure anti-oestrogen
  • It may offer advantages over tamoxifen by decreasing tumour cell invasion and the stimulation of occult endometrial carcinoma
• Raloxifene is an antitumour agent in animals
  
  • It is an agonist in bone but has no activity in the breast or uterus
  • It is used in the treatment of osteoporosis in post-menopausal women

Question 14

What are the problems associated with using Tamoxifen in prevention of breast cancer?

Answer 14

• Endometrial cancer
• Stroke
• DVT
• Cataracts
• To overcome these problems, prevention trials are being conducted with:
  
  • Raloxifene/Faslodex (SERMs)
  • Aromatase inhibitors

Question 15

Explain the use of aromatase inhibitors in breast cancer.

Answer 15

• In post-menopausal women, the major source of oestrogen derives not from the ovaries but from the conversion of the adrenal hormones (androstenedione and (to a lesser extent) testosterone) to oestrone
• The enzymatic conversion occurs at extra-adrenal or peripheral sites such as fat, liver and muscle
• The conversion is catalysed by the aromatase enzyme complex
• Aromatase consists of a complex containing a CYP450 heme containing protein as well as flavoprotein NADPH CYP450 reductase
• Aromatase catalyses three separate steroid hydroxylations involved in the conversion of androstenedione to oestrone
• Aromatase metabolises androstenedione to oestrone sulfate, which then circulates in the plasma
• Types of aromatase inhibitors:
  
  • Suicide Inhibitors
    
    • ​Initially compete with the natural substrate (andostenedione or testosterone) for binding to the active site
    • The enzyme then specifically acts on the inhibitor to yield alkylating species, which form covalent bonds at or near the active site of the enzyme
    • Through this mechanism the enzyme is irreversibly inactivated
    • Example of suicide inhibitor - Exemestane
      
      • ​Single dose results in a major drop in plasma oestrogens
      • Side effects are milk - e.g. hot flushes, nausea, fatigue
  • Competitive Inhibitors
    
    • ​Binds reversibly to the active site of the enzyme and prevent product formation only as long as the inhibitor occupies the catalytic site
    • Exampe of competitive inhibitor: Anastrozole

Question 16

What is the use of progestins in breast cancer?

Answer 16

• Progesterone is the dominant naturally occurring progestin
• The poor absorption of progesterone has been overcome by some of the synthetic derivatives progestins
• Progestins response in the breast is complex and influences both proliferation and differentiation function
• Progestin are used in the endocrine treatment of uterine and breast cancer witih clinically proven anti-neoplastic properties.
• Progestin therapy for metastatic breast cancer has been used principally as a second or third-line therapy following selective oestrogen
• The main progestin used for metastatic breast cancer has been megestrol acetate
  *

Question 17

What is the screening process for breast cancer?

Answer 17

Question 18

Describe the patient history of breast cancer.

Answer 18