Hormone receptors and cancer

What is the main role of steroid hormone receptors in cancer?

They regulate gene transcription that controls cell proliferation, survival, and apoptosis; dysregulation can drive cancer growth (especially ER and AR).

Which cancers are most strongly hormone receptor–dependent?

• Breast cancer (estrogen receptor, ER)

• Prostate cancer (androgen receptor, AR)

Why are hormone receptors important clinically in cancer?

They act as diagnostic markers, prognostic indicators, and therapeutic targets.

What is the normal function of androgens in the prostate?

They regulate survival, growth, and apoptosis of prostate cells.

What drives prostate cancer growth initially?

Androgen receptor (AR) signalling.

What is PSA used for?

Screening and monitoring prostate cancer (PSA = prostate-specific antigen).

What PSA level is considered suspicious?

4–10 ng/mL

What PSA level is considered dangerous?

>10 ng/mL

What is the Gleason score?

A histological grading system that predicts prostate cancer aggressiveness.

What does a Gleason score of 6 mean?

Low-risk prostate cancer (3 + 3)

What does a Gleason score of 8–10 indicate?

High to very high-risk aggressive cancer

Key risk factors for prostate cancer?

• Age (especially 75–79)

• Family history

• Black ethnicity (higher risk)

• BRCA1/2 mutations

• Obesity

• Hormonal imbalance (↑ testosterone, IGF-1)

Main treatments for prostate cancer?

• Prostatectomy

• Radiotherapy

• Hormone therapy (anti-androgens, LHRH blockers)

• Chemotherapy (docetaxel, paclitaxel, cabazitaxel)

What do anti-androgens do?

Block AR signalling (e.g. bicalutamide, enzalutamide)

What is Zytiga (abiraterone)?

A CYP17 inhibitor that blocks androgen synthesis

Main mechanisms of AR therapy resistance?

• AR mutations (ligand-independent activation)

• AR gene amplification

• AR overexpression

• Coactivator changes (e.g. SRC-2/NCOA2)

• AR splice variants (e.g. AR-V7)

• Epigenetic silencing (EZH2)

• Bypass signalling (IGF-1, EGF, IL-6, PI3K/AKT)

What is AR-V7?

A constitutively active AR splice variant that drives androgen-independent prostate cancer.

What is “outlaw pathway” activation?

Ligand-independent activation of AR via growth factors and cytokines.

What percentage of breast cancers are ER-positive?

~70%

What are estrogen receptors involved in?

Regulation of gene transcription controlling proliferation and metabolism.

Where is ERα mainly expressed?

Breast, uterus, bone, cardiovascular system

Where is ERβ mainly expressed?

Ovary and urinary tract

How does estrogen contribute to cancer development?

• Stimulates proliferation of mutated cells

• Increases chance of DNA replication errors

• Promotes accumulation of mutations over time

Why does estrogen increase breast cancer risk?

It increases cell proliferation → higher chance of DNA replication errors in mutated cells

What are the main classes of ER-targeted therapies?

• Aromatase inhibitors (AIs)

• SERMs (e.g. tamoxifen, raloxifene)

• SERDs (e.g. fulvestrant)

What do aromatase inhibitors do?

Block estrogen synthesis

What is a SERM?

A drug that acts as an estrogen agonist in some tissues and antagonist in others.

Example of a SERM used in breast cancer?

Tamoxifen

How does tamoxifen work in breast tissue?

Blocks estrogen receptor → prevents proliferation

Why can tamoxifen increase uterine cancer risk?

It acts as an estrogen agonist in uterine tissue

What is a SERD?

A drug that binds ER and promotes its degradation

Example of SERD?

Fulvestrant

Benefits of SERMs (e.g. tamoxifen)?

• Reduce breast cancer recurrence

• Improve bone density

• Improve lipid profile

Major risks of tamoxifen?

• Uterine cancer

• Blood clots

Why is raloxifene used?

Prevents osteoporosis and reduces breast cancer risk in postmenopausal women

Why do ER+ and AR+ cancers respond to hormone therapy?

They depend on hormone-driven transcription for growth and survival.

Why do hormone-dependent cancers become resistant?

They acquire mutations or activate alternative signalling pathways (bypass mechanisms).

What is the central idea of hormone receptor–targeted cancer therapy?

Block hormone signalling to stop transcriptional programs that drive tumor growth.

What is the unifying concept of this lecture?

Hormone receptors (ER and AR) drive cancer progression, and targeting their signalling pathways is a cornerstone of modern cancer therapy—but resistance commonly emerges through receptor alterations or bypass signalling.