Lecture 3 - Hormonal basis of cancer Flashcards
what are cancers that are regulated by hormones?
Breast, endometrium, ovary, prostate, testes, thyroid, osteocarcinoma
Cervical cancer, vaginal cancer etc.
Exogenous and endogenous hormones drive cell division.
The more cells divide the more chance they get more mutations,.
Contraceptives, HRT small increased risk of HR cancer.
give examples of sex hormones and their descriptions
breast cancer - related organs is ovaries and relate chrome is oestrogen, progesterone
thyroid cancer = related organ is thyroid, pituitary gland. related hormones are T3, T4, TSH
bone cancer - related organ is pituitary gland, related hormone is GH
ovarian cancer - related organ is ovaries, uterus, Fallopian tubes. related hormones are oestrogen and progesterone
prostate cancer - prostate, tests, testosterone and androgen
what are possible carcinogenic mechanisms of oestrogen?
- Estrogen binds to receptor and sends grow signal to cell
- Estorgen also directly induces cell growth pathways such as ERK, PI3K
- Estrogen metabolism makes nasty metabolites which can cause DNA damage
- Estrogen downregulates DNA damage repair so cancer cells continue to grow gathering more mutations
what are risk factors for breast cancer?
Early menarche- internal hormones (hormones in body earlier- longer?)
Late menopause- internal hormones
Post-menopausal obesity – fat cells make extra
hormones and GF. hormones and GF tell cells in out body to divide more, increases changes of cancer cells being produced which can then divide and turn into tumour.
Hormone replacement therapy – (additional hormones in the body
describe combined and single HRT with cancer
Hormone replacement therapy (HRT) slightly increases the risk of breast cancer, ovarian cancer, and
sometimes womb cancer.
- combined HRT slightly increases the risk of breast cancer- higher risk the longer the use
-combined HRT slightly increases the risk of ovarian cancer. When HRT is stopped, the increased risk
starts to go back down.- combined HRT does not affect womb cancer risk.
For Oestrogen only HRT- slight increase in risk for breast and ovarian
- significant risk of womb cancer
HRT is an effective treatment for symptoms of menopause. For most people, the benefits of taking HRT
outweigh the risks.
describe breast cancer
2nd most common cancer death.
improvement in detection, iso incidence has increased, leading to improved treatment and mortality decreased
how do we target the oestrogen receptor?
Reduce/block the formation of estrogen(s)?
Aromatase inhibitors e.g. Aromasin
Block estrogen interaction with ER?
ER antagonists e.g. Tamoxifen
Explain ER breast cancers types and treatment for it.
75% of breast cancer are ER psotive. these women can be treated with hormone replacement therapy
ER positive breast cancer is when the caner cells have oestrogen receptors which allow oestrogen to bind to them and cause cell proliferation. However, ER+ can be treated with HRY such as tamoxifen which inhibits the oestrogen receptor.
ER negative breast cancer is when the cancer cells don’t have oestrogen receptors and so is not controlled by oestrogen and there is cell proliferation
what are good and bad effects of tamoxifen?
tamoxifen also recduces recurrence rate
good effects:
reduces risk of ER+ breast acne, more effective against invasive breast cancer, benefits persist when its no longer taken, strengthens bones and lowers LDL cholesterol
bad effects: increases risk f uterine cancer, increases risk of blood clots, causes menopause-like symptoms
what are differences in tamoxifen and ai inhibitors?
normally, androgens produce oestrogen’s which bind to ER and eventually increase proliferation.
Tamoxifen prevents
Binding or E to ER
AI prevents production
Of Es
explain HER2 and breast cancer
HER2 is a protein found in excess in a subtype of breast cancer.
in normal cell, HER2 receptors send signals telling cells to grow and divide.
in cancerous breast/ stomach cells, too many HER2 receptors send more signals, causing cells to grow too quickly
Herceptin (trastuzumab) binds to the HER2 proteins receptors and decreases the signals for cells to divide. Binding of her pectin to cells also induced anti-tumour response.
what are other mechanism of action of Herceptin?
- Antibody dependent cell-mediated cytotoxicity (ADCC)
- Lysis of HER2-expressing cells through complement (C’) activation
most common side effects are: infusion reactions (itching, flushing, nausea), headache & abdominal pain.
what is triple negative breast cancer?
lack of oestrogen, progesterone and HER2 - no targeted therapies
much more aggressive. younger age diagnosis, high grade, large tumour size and aggressive relapse
what are treatment options for hormone replacement positive breast cancer patients?
surgery, chemo, radiotherapy,
targeted: tamoxifen and other anti-endocrine therapy
what are treatment options for HER positive breast cancer?
surgery chemo, radio
targeted: Herceptin and other anti-HER2 therapy
what are triple negative BC treatments
surgery, chemo, no targeted theory
describe options for chemotherapy before vs after surgery
Option: chemotherapy before surgery to shrink a large cancer enough to make an operation possible. Or it might mean that you can have an area of the breast removed, instead of needing a mastectomy.
Option: Chemotherapy after the operation to reduces the risk of the breast cancer coming back.
combination of chemotherapy drugs
what are common combination chemotherapy drugs given?
F - Fluorouracil (5FU)
E- Epirubicin
C - Cyclophosphamide
T - Docetaxel (Taxotere)
describe prostate cancer
most common cancer diagnosed and 2nd most common cause of death due to cancer in men
in first instance, prostate cancer is locally invasive and androgen dependant. all patients have at least 5 year survival program followup diagnosis.
prosate cancer recurs after treatment and spreads t other parts of body. continues to grow when male hormones are reduced. incurable and survival program is 16-18 months
what are treatment strategies for prostate cancer?
All strategies coupled with active surveillance – monitoring the levels of Prostate Specific Antigen (PSA)
Surgery – radical prostatectomy
Radiotherapy – brachytherapy
Chemotherapy
Androgen Depravation Therapy (ADT)
- AR antagonists (steroidal vs. non-steroidal; e.g. chlormadinone acetate vs. flutamide)
- Inhibitors of androgen synthesis e.g abiraterone – inhibits extragonadal and intratumoral synthesis of androgens
what is the role of androgens in promoting prostate cell growth?
The major androgen in males
is testosterone
Other androgens include DHT
Androgens are also the
precursors to estrogen in males
and females
what are the principles of ADT?
prostate cells are physiologically dependant on androgens to grow, function and proliferate.
testosteron is the primary male androgen. the testes are a major source of testosterone.
dihydrotestosterone DHT is a metabolite of testosterone and is a more potent androgen.
testosterone does not cause prostate cancer but promotes and encourages growth
androgen deprivation can help induce apoptosis ir prevent further growth by surgical or medical castrstration: stop reproduction of testosterone or
anti-androgen therapy; inhibits the action of testosterone preventing its interaction with the receptors on the prostate cancer cells
what are androgen biosynthesis?
used as anti-androgen theory:
drugs inhibits androgen biosynthesis such as ketoconazole, abiraterone, TAK-700 and TOK-001
what is androgen receptor blockers
androgen receptor blockers prevent testosterone(androgen) from binding to the androgen receptors causing less testosterone which causes the cancer.
these drugs include: bicalutamide, nilutamide, flutamide, anzalutamide and ARN-509
what is the mechanism of action of enzalutamide?
enzalutamide prevents the binding of androgens to testosterone to the androgen receptor. this inhibits androgen nucleus translocation and inhibits Androgen mediated DNA binding
