Hormones and cancer Flashcards
What are the hormone related cancers?
Breast, endometrium, prostate, testis, ovary, thyroid and osteosarcoma
What are the hormones typically involved in hormone related cancers?
Oestrogens and androgens
What is unique about hormonally driven cancers as opposed to other forms of cancer?
There is no need for an initiating factor
What is the evidence for the role of hormones in cancer development?
In cell culture hormones can promote cell proliferation and survival such as oestrogens promoting breast cancer cell proliferation
Various tumour types are induced in animals by different hormone treatments for example oestrogens can induce and promote mammary tumours in rodents
They increase the number of tumours and the rate of their development
Removing the hormone source or administering an anti-oestrogen drug can prevent or slow the growth of tumours
What are the possible roles for oestrogens in the multistage process of carcinogenesis?
Hormones act mainly in the promotion and transformation steps, some hormones may be important at most stages
Hormones act mainly in the promotion and transformation steps, some hormones may be important at most stages
Increased cell division and proliferation
Increased DNA synthesis and gene expression
Inducing oestrogen receptors
Shifting the dormant cells from G0 to G1-S phase
Inhibition of apoptosis
Increasing formation of free radicals
Promoting vascularisation
How can hormones interact with growth factors and oncogenes?
Oestrogens can activate their own receptors as well as epidermal growth factor receptors and myc, ras and fas oncogenes
Oestrogens are thought to stimulate the proliferation of breast cancer cells by regulating the synthesis of stimulatory and inhibitory growth factors
What does the overall evidence say about oestrogens and androgens in cancer?
That they are weak carcinogens, (they cannot be strong carcinogens as there would be no evolutionary advantage then)
This is based on endocrinological evidence which is supportive but inconsistent
Association with cancer risk factors this is indirect evidence provocative but not conclusive support
Surgical procedures which remove hormone sources
Anti-hormone agents used therapeutically
Effects of exogenous hormones on the incidence of cancer
What is the endocrinological evidence which suggests hormones may play a role in cancer?
Endocrinological evidence have not yielded consistent evidence that any oestrogen is associated with an increased risk of cancer
However several studies have shown that those with higher levels of serum oestrogen have higher levels of breast cancer
Serum testosterone is not associated with prostate cancer risk
Levels of steroids in urine and plasma only provide an indirect, and not necessarily an accurate indication of tissue concentrations
A hyperoestrogenic environment may stimulate existing tumours so that they become quickly apparent
What is oestrogen-responsive breast cancer?
Oestrogen binds reversibly and with high affinity to the estrogen receptor
6-10% of normal breast epithelial cells are ER+
Approximately 70% of primary breast cancers are ER+ which strongly indicates that these are hormone-responsive cancers
The majority of ER-positive tumours respond well to hormone therapy and have favourable outcome
ER-negative tumours do not respond well to hormone therapy and have poorer prognosis with a greater prosperity to metastasis
What is the purpose of oophorectomy in cancer therapy?
removal of major sources of estrogen in premenopausal women
What is the purpose of Adrenalectomy in cancer therapy?
Elimination of the major source of androgen precursors in postmenopausal women
What is the purpose of hypophysectomy in cancer therapy?
This removes pituitary hormones including both ovarian and adrenal hormones
What is the purpose of GnRH-agonists in cancer therapy?
Downregulates gonadotropin-releasing hormones which drives production of oestrogens
What is the purpose of aromatase inhibitors in cancer therapy?
This prevents the biosynthesis of oestrogens from androgens
What is the purpose of Anti-estrogen/SERM in cancer therapy?
This blocks oestrogen at its receptor
What are the strategies for therapeutically targeting the oestrogen receptor?
Selective oestrogen receptor modulators (SERMs) can block the ER in some tissues (tamoxifen)
Pure oestrogen antagonists can block and destroy the ER (Fulvestrant)
Aromatase inhibitors block the synthesis of new oestrogen
How can oral contraceptive and hormone replacement therapy play a role in hormonally driven cancer?
Recent studies indicate that a modest increase in the risk of breast cancer was associated with current and recent combined oral contraceptive use however there is no evidence that this excess in risk continued to persist 10 years after cessation of use
Combined oral contraceptives reduce the risk of ovarian and endometrial cancers
Several studies have shown a slight rise in breast cancer risk in women taking hormone replacement therapy, this risk increases in relation to increasing duration of use
One problem with these studies is that not all oestrogens and progestagens are used with the same dosage, route of administration and do not show the same bioavailability and tissue effects
What role might environmental oestrogens and endocrine disruptors play in hormonally driven cancer?
There has been a recent interest in environmental hormone or endocrine disruptors particularly environmental oestrogens which mimic hormone action
They have been linked to an increase in disorders or reproductive development and function in the human male and in some species of wildlife
Breast cancer has also been linked to exposure to various environmental chemicals or their metabolites
A range of widely used man made chemicals can act as weak oestrogens
However the majority of endocrine disruptors no evidence of increased cancer risk in humans has been established
What is diethylstilbestrol?
This is a synthetic form of estrogen that was given to pregnant women from 1940-1971 to prevent premature miscarriage
Women who took this during pregnancy had an increased risk of breast cancer
Exposure in utero to diethylstilbestrol resulted in an increased incidence of breast, endometrial and cervico-vaginal carcinomas in young woman and testicular abnormalities in men
What is Bisphenol A?
Bisphenol A or BPA has been shown to promote tumour cell growth in vitro and tumour growth in animal studies
Is detectable in the urine of approximately 90% of the US population
Whether it affects cancer growth in humans is controversial and there has been no convincing evidence linking BPA to human cancer incidence
However an unexplored area is what it may do to the in utero environment
Why is it difficult to prove that environmental chemicals are linked to cancer?
Inherently lower potency
Varied nature
Cumulative and combined effects might be crucial
Hard to measure accurately
What are phytoestrogens?
These are things such as soya isoflavones, genistein and daidzein which are plant derived non-steroidal oestrogen mimics that may reduce cancer
Breast and prostate cancer are less prevalent in Eastern countries who consume more soy products resulting in there possibly being a weak inverse association between soy food consumption and breast cancer
This assumption is more obvious in Asian populations where soy consumption is much higher than it is in western populations
There affects are still an area of controversy as it may act as a weak oestrogen but anti-oestrogen effects have also been reported or they may have a role in altering the metabolism and availability of endogenous oestrogens
What are the established risk factors for breast cancer?
Alcohol consumption (2 drinks/day) BMI in the 8-th percentile Estrogen-Progesterone Rx Menarche before 12 years Menopause after 55 years Nulliparous, parous after 30 years Breast density Adult height
What are the breast cancer risk factors which are unclear?
High birth weight Diet Night shift/Late at night Tobacco smoke Environmental chemicals Stress
What are the controversial risk factors for breast cancer/
Abortions
Bras
Deodorants
Breast Implants
