Lecture 8 - Cancer Endocrinology - Prinns Flashcards
Describe mechanisms whereby steroids can separately affect a) initiation, b) promotion,
and c) progression of cancers in hormone-dependent tissues.
What is the molecular basis for tissue-specific responses to SERMs?
- Initiation: non SR mediated genotoxic effects.
- Promotion: In tissues with SRs, steroids are co-carcinogens that promote dev of tumors by INDUCING INITIATORS!!
- Progression: Through steroid receptor pathway, steroids are involved in TUMOR MAINTAINANCE!!!
SERM: can be ag/antag based on co-activators present.
EX Tamoxifen prevents breast cancer because ER is off, but causes uterine cancer because ER is activated by co-receptors
Different coreceptors = different ER conformational change = either on or off
- What are three known risk factors for prostate cancer? (3 points)
- Ethnicity - highest in African American males, lowest in asians in US
- Gene-environment. Env: Diet, env exposure
- Age
- Family history, genetic component
Protection: castration, eunich
- The prostate gland is a hormone-dependent tissue. What hormones are involved
in regulating prostate growth? (3 points)
- FSH, LH, T
- ACTH, DHEA, AD
***3. While advanced, castration-resistant prostate cancer (CRPC) evades first-line
endocrine therapy, it still depends on androgen receptor (AR) for continued growth.
Identify at least three adaptations of the cancer cell that drive this process (6
points
Castration Resistant Prostate Cancer
- still AR dependent
1. Cancer cell has mRNA splice variants in AR that lack ligand binding domain so they are always on, in the absence of a ligand.
2. ARs are amplified/overexpressed
3. Non-canonical AR signaling - cell finds a way to bypass AR to activate the same regulatory genes.
Link between hormones and cancer?
- many common cancers develop in areas that are under regulation by hormones.
- Breast, prostate, thyroid, kidney
Endocrine Regulation of Prostate Growth
- Hypothalamus: GnRH, CRH
- Pituitary: LH, FSH -> testes -> T -> Prostate
- Pituitary: ACTH -> adrenals -> DHEA, AD -> Prostate
Effects of T on Prostate
Prostate growth is entirely dependent on T from the Testes.
- Castration: prostate can grow back w exogenous T
What does the pituitary produce?
- LH and FHS -> testes (T, E) and ovaries (progesterone, estrogen)
- ACTH -> adrenal (cortisol, androgens)
- TSH -> thyroid
Progression of Prostate Cancer
- Prostate cancer develops in the posterior zone (PZ) region
- It is ANDROGEN DEPENDENT (AR)
= PIN: prostate cells in epith have transformed but are still confined to BM
1. INITIATION.
2. PROGRESSION - AR, progresses into latent carcinoma, confined to prostate
3. METASTASIS: - can now go from AR to AI.
- spreads to bone
Prostate Cancer Biomarker
PSA: Ab produced in the semen
- Isnt a good biomarker bc it is also present in latent carcinoma.
Contribution of polymorphisms to cancer
- higher activity variants, ex in enzymes that play a role in hormone synth, lead to cancer
- lower activity variants confer protection
- a5 reductase converts T to estrodiol
Cancer Initiators and Promotors
- Initiator: cell has a mutation but growth is restrained
- Promoter: growth is now unrestrained, active mutation can proliferate
- Need both, I before P,
- Depends on dosage, timing and sequence
Hormones as co-carcinogens
- Sensitization - stimulating cell division
- Classical promotion - help growth
- Acceleration and Progression of tumor growth
Endocrine Therapy
- Steroidogenic Enzyme Inhibitors
- inhibits breakdown of T to estrogen, estrodial - Receptor Antagonists
- block estrogen receptor
Steroid Receptors
- ligand binding domain, ZF DNA binding domain
- transcription is influenced by a bunch of activators and repressors
- these coregulators mediate differences in SR function
- chromatin modifications occur in tandem to influence expression
ER Ligand binding domain
- H12 helix is the molecular switch.
- when it flips over, co-regulators can bind -> expression
- an antagonist for ER blocks H12 from flipping over
SERM
Selective Estrogen Receptor Molecules
- Small molecules that bind to ER proteins and behave differently in different tissues
- can be agonist or antag depending on coactivators
Peptide Hormones
- GH: growth hormone
- IGF-I: mediates GH action,
May be new targets for anti-cancer agents
Emerging Therapies for CRPC
- immunotherapy
- targeting peptide hormones
***Describe how AR regulation contributes to prostate cancer growth and progression. Discuss the role of AR in androgen independent prostate cancer
“androgen, uh, finds a way.”
- prostate cancer is a 100% organ confined disease and is AR positive. The disease is initially dependent on androgen, but as it progresses, it becomes androgen independent, but still retains AR.
- Androgen is a steroid that acts on ARs and phosphorylates them, allowing them to dimerize and then bind to regulatory regions on the DNA to influence transcription. Promotes cell proliferation and survival.
- The affects of androgen may persist even after the disease progresses to androgen independence, where it is no longer dependent on the hormone.
- ARs may become mutated to be constitutively active, overexpressed, or may develop non-canonical signalling, so even without androgen present, the cell still experiences its transcriptional effects.
***How are hormones co-carcinogens?
- SENSITIZATION: they stimulate division and expose dividing cells to initiating agents. (ex: mistake in replication)
- CLASSICAL PROMOTION: hormones increase the incidence of tumor dev FOLLOWING exposing to initiators.
- ACCELERATION OF TUMOR GROWTH: hormones increase expression of growth factors, regulate cell cycle, and crosstalk w other pathways.
