Lecture 34 – Tumor Suppressors, Proto-Oncogenes, Oncogenes

Q: What are tumor suppressors?

Genes encode proteins that normally suppress tumor formation, suppress cell motility, repair DNA damage, and limit cell proliferation. They act as the "brakes" on the cell.

Q: What are proto-oncogenes?

Normal genes that encode proteins promoting cell proliferation. They act as the "accelerators" of the cell.

Q: What is an oncogene?

Abnormally expressed or mutated form of a proto-oncogene that promotes the loss of growth control and drives cancer progression.

Q: Name five examples of tumor suppressors and their functions.

p53 — transcription factor and guardian of the genome (G1 arrest, apoptosis);

pRB — cell cycle regulator preventing premature S-phase entry;

BRCA1/BRCA2 — DNA repair proteins;

phosphoinositide phosphatase — shuts down phospholipid-based signalling;

E-cadherin — cell junction protein maintaining tissue integrity via adherens junctions.

Q: What is Knudson's two-hit hypothesis?

Both copies (alleles) of a tumor suppressor gene must be inactivated before cancer arises. A single functional copy is sufficient to suppress tumor formation.

Q: Why are patients with one inherited RB mutation at higher risk for other cancers?

Every cell in their body already carries one mutant RB allele, the chance of a second mutation occurring is higher not just in the eye but in other tissues as well, increasing lifetime cancer risk.

Q: How does tumor suppressor gene compare to proto-oncogenes?

Both copies of a tumor suppressor must be inactivated (loss of function, recessive). For proto-oncogenes, only one copy needs to gain an oncogenic mutation for a cancer-promoting effect (gain of function, dominant).

Q: Why does p53 status matter for cancer treatment?

Tumors with wild-type p53 respond well to DNA-damaging treatments (chemotherapy/radiation) because p53 triggers apoptosis. Tumors with inactive/mutant p53 are resistant to these treatments because the apoptotic pathway is not activated.

Q: How does elephants' resistance to cancer relate to tumor suppressors?

Despite having many more cells (theoretically greater cancer risk), elephants have approximately 20 copies of the TP53 tumor suppressor gene, which may be responsible for their lower cancer rates.

Q: What are the three mechanisms by which a proto-oncogene can become activated to an oncogene?

(1) Mutation or deletion in the coding region — changes protein function (e.g., Ras always bound to GTP).

(2) Gene duplication — increased amounts of protein stimulate the cell cycle.

(3) Chromosomal translocation — proto-oncogene is placed under a highly active regulatory sequence, or two coding regions fuse to create a new protein with a new function.

Q: How can chromosomal translocation activate a proto-oncogene?

(1) the coding part of the gene is placed next to a highly active regulatory sequence from another gene, causing overexpression;

(2) the coding part fuses with another protein-coding region, producing a novel fusion protein with a new, oncogenic function.

Q: Why might fusion proteins from translocations be good drug targets?

Highly specific to the cancer cell (don't exist in normal cells) making them easy to target without affecting healthy tissue.

Q: What types of proteins are encoded by proto-oncogenes?

Growth factors and their receptors (e.g., EGFR); protein kinases or activators of kinases (e.g., SRC, FYN, Ras); cell cycle control proteins (e.g., cyclin D1); proteins regulating apoptosis/survival; transcription factors (e.g., Fos and Jun from the MAPK pathway).

Q: What is ErbB2/HER2 and why is it important in cancer?

A receptor related to EGFR that is overexpressed in some breast cancers, driving proliferation. It is targeted by Herceptin (trastuzumab), the first molecule-targeted cancer drug, which blocks the receptor from being activated.

Q: How do SRC, FAK, and Ras relate to adhesion-dependent proliferation?

Activate the MAPK cascade to promote adhesion-dependent cell proliferation and survival. If oncogenically activated, they can enable anchorage independence.

Q: Could the phosphatase that shuts off each MAPK be a tumor suppressor? Why?

Yes — because these phosphatases normally limit MAPK signalling. If they are lost or inactivated, the MAPK cascade stays active, promoting uncontrolled cell growth, making them protective (tumor-suppressive) by function.

Q: Classify each: E-cadherin, FAK, p53, BRCA1/2, pRB, Fos and Jun, RAS, EGFR/ErbB2/HER2.

Tumor suppressors: E-cadherin, p53, BRCA1/2, pRB.

Proto-oncogenes: FAK, Fos and Jun, RAS, EGFR/ErbB2/HER2.

Q: How many mutations are generally needed for a cell to become cancerous?

5–7, but even a single mutation can cause some loss of growth control.

Q: Summarize the relationship between tumor suppressors and oncogenes in cancer.

Both copies of tumor suppressor(s) must be inactivated (brakes removed) AND proto-oncogenes must be activated to oncogenes (accelerators stuck on) for cancer to arise. Tumor suppressors restrain growth; oncogenes drive growth and survival.