Lecture 8 - Cancer Endocrinology - Prinns

Question 1

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?

Answer 1

1. Initiation: non SR mediated genotoxic effects.
2. Promotion: In tissues with SRs, steroids are co-carcinogens that promote dev of tumors by INDUCING INITIATORS!!
3. 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

Question 2

1. What are three known risk factors for prostate cancer? (3 points)

Answer 2

1. Ethnicity - highest in African American males, lowest in asians in US
2. Gene-environment. Env: Diet, env exposure
3. Age
4. Family history, genetic component
   Protection: castration, eunich

Question 3

2. The prostate gland is a hormone-dependent tissue. What hormones are involved
   in regulating prostate growth? (3 points)

Answer 3

• FSH, LH, T

- ACTH, DHEA, AD

Question 4

***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

Answer 4

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.

Question 5

Link between hormones and cancer?

Answer 5

• many common cancers develop in areas that are under regulation by hormones.
• Breast, prostate, thyroid, kidney

Question 6

Endocrine Regulation of Prostate Growth

Answer 6

1. Hypothalamus: GnRH, CRH
2. Pituitary: LH, FSH -> testes -> T -> Prostate
3. Pituitary: ACTH -> adrenals -> DHEA, AD -> Prostate

Question 7

Effects of T on Prostate

Answer 7

Prostate growth is entirely dependent on T from the Testes.

- Castration: prostate can grow back w exogenous T

Question 8

What does the pituitary produce?

Answer 8

• LH and FHS -> testes (T, E) and ovaries (progesterone, estrogen)
• ACTH -> adrenal (cortisol, androgens)
• TSH -> thyroid

Question 9

Progression of Prostate Cancer

Answer 9

• 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

Question 10

Prostate Cancer Biomarker

Answer 10

PSA: Ab produced in the semen

- Isnt a good biomarker bc it is also present in latent carcinoma.

Question 11

Contribution of polymorphisms to cancer

Answer 11

• 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

Question 12

Cancer Initiators and Promotors

Answer 12

• 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

Question 13

Hormones as co-carcinogens

Answer 13

1. Sensitization - stimulating cell division
2. Classical promotion - help growth
3. Acceleration and Progression of tumor growth

Question 14

Endocrine Therapy

Answer 14

1. Steroidogenic Enzyme Inhibitors
   - inhibits breakdown of T to estrogen, estrodial
2. Receptor Antagonists
   - block estrogen receptor

Question 15

Steroid Receptors

Answer 15

• 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

Question 16

ER Ligand binding domain

Answer 16

• H12 helix is the molecular switch.
• when it flips over, co-regulators can bind -> expression
• an antagonist for ER blocks H12 from flipping over

Question 17

SERM

Answer 17

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

Question 18

Peptide Hormones

Answer 18

• GH: growth hormone
• IGF-I: mediates GH action,

May be new targets for anti-cancer agents

Question 19

Emerging Therapies for CRPC

Answer 19

• immunotherapy

- targeting peptide hormones

Question 20

***Describe how AR regulation contributes to prostate cancer growth and progression. Discuss the role of AR in androgen independent prostate cancer

Answer 20

“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.

Question 21

***How are hormones co-carcinogens?

Answer 21

1. SENSITIZATION: they stimulate division and expose dividing cells to initiating agents. (ex: mistake in replication)
2. CLASSICAL PROMOTION: hormones increase the incidence of tumor dev FOLLOWING exposing to initiators.
3. ACCELERATION OF TUMOR GROWTH: hormones increase expression of growth factors, regulate cell cycle, and crosstalk w other pathways.