Breast Cancer Lecture 5: DNA Repair and Genomic Integrity

Breast Cancer and Genomic Integrity

• Family history influences breast cancer risk, with more relatives having breast cancer increasing the individual's risk.
• Breast cancer in young close relatives is also a risk factor.

BRCA1

• Linked to a DNA marker on chromosome 17.
• Truncation mutations are common in families with multiple cases.
• Relatively large gene, making it a big target for mutation.
• Over 1500 distinct germline mutations reported.
• BRCA1 families do not show cases of male breast cancer.
• BRCA1 breast tumors tend to be high grade and look unusual.
• BRCA1 ovarian tumors are invasive epithelial tumors.

BRCA1 Structure and Function

• The ring domain interacts with other proteins via the zinc finger.
• The NLS (nuclear localisation signal) indicates that the protein functions in the nucleus.
• The BRCT domain is seen in proteins involved in the cell cycle and checkpoints responding to DNA damage.
• BRCA1 localizes to DNA damage regions and is integral to repair.
• It co-localizes with other DNA repair proteins, including Rad51.
• BRCA1 promotes homologous recombination, a less error-prone repair process.

BRCA1 and Homology Directed DNA Repair

• BRCA1 acts within a complex crucial for homologous recombination.
• Resection of one DNA strand is necessary for homologous recombination.
• BRCA1's exonuclease activity is required for resection.
• If BRCA1 is damaged, non-homologous recombination may occur, leading to mutations.

BRCA1 and BARD1

• BRCA1 and BARD1 form a heterodimer with E3 ubiquitin ligase activity.
• The complex activates and recruits proteins to repair DNA lesions.
• BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase and excluding CDC25 from the nucleus.

BRCA2

• Located on chromosome 13q12-13.
• Relatively large gene, widely expressed.
• Mutations in BRCA2 increase breast cancer risk in males to 5% (x200 that of the general population).
• 14% of male breast cancers are derived from BRCA2 mutations.
• Analysis of large families indicates a 70% risk by age 70.
• Other tumors in BRCA2 families include prostate, pancreas, and lung.

BRCA2 Structure and Function

• Less diverse than BRCA1.
• Transcriptional activation region.
• Multiple sites bind to Rad51.
• Nuclear localisation signal.
• BRCA2 helps BRCA1 carry Rad51.

Roles for BRCA2

• Disruption of BRCA1 and 2 leads to similar phenotypes.
• BRCA2 is necessary for the repair of DSBs by gene conversion.
• BRCA2 binds tightly to Rad51 via the BRC region, indicating a direct role in recombination repair.

BRCA2 and Rad52 in Homologous Recombination

• DNA damage/replication arrest causes DSBs.
• DSBs activate DNA damage signaling kinases (ATM or ATR).
• Phosphorylated BRCA2 releases Rad52, allowing it to bind to DNA and repair the damage.

Cell Cycle and Checkpoint

• Checkpoint arrest following damage is less affected by the disruption of BRCA2 than 1.
• BRCA1 may link BRCA2 DNA repair functions to the pathways that signal incomplete replication or damage.
• BRCA2 may play a role in the repair process by loading Rad51 onto BRCA1.

Mutations and Allele Penetrance

• Penetrance: the ability of a mutation to cause clinical disease in an individual carrying a specific allele.

Non-BRCA Derived Tumors

• Rare familial conditions that result in breast cancer include Fanconi Anemia and Ataxia Telangectasia (AT).
• BRCA type tumors are recognizable due to specific phenotypes, including basal tumors, negative EGFR expression, and lymphocytic infiltration.

Therapy and Treatment

• Surgery, radiotherapy, chemotherapy, and hormonal therapy (anti-oestrogen therapy) are treatment options.
• Herceptin targets the ERBB2 receptor, effective in 30% of early-stage breast cancer.
• Hormone resistance can be acquired or intrinsic.

Hormone Treatment

• 75% of sporadic tumors are Oestrogen receptor (ER) positive.
• Tamoxifen is an oestrogen agonist, effective in 70% of ER-positive and/or progesterone-positive tumors.
• However, 30-50% relapse, and tamoxifen can only be taken for 5 years.

Hormone Resistance

• Intrinsic resistance: tumors that do not express receptors will be resistant.
• Acquired resistance: tumors that stop expressing the receptor and grow in the absence of oestrogen.

Breast Cancer and Genomic Integrity

• Family history influences breast cancer risk, with more relatives having breast cancer increasing the individual's risk.
• Breast cancer in young close relatives is also a risk factor.

BRCA1

• Linked to a DNA marker on chromosome 17.
• Truncation mutations are common in families with multiple cases.
• Relatively large gene, making it a big target for mutation.
• Over 1500 distinct germline mutations reported.
• BRCA1 families do not show cases of male breast cancer.
• BRCA1 breast tumors tend to be high grade and look unusual.
• BRCA1 ovarian tumors are invasive epithelial tumors.

BRCA1 Structure and Function

• The ring domain interacts with other proteins via the zinc finger.
• The NLS (nuclear localisation signal) indicates that the protein functions in the nucleus.
• The BRCT domain is seen in proteins involved in the cell cycle and checkpoints responding to DNA damage.
• BRCA1 localizes to DNA damage regions and is integral to repair.
• It co-localizes with other DNA repair proteins, including Rad51.
• BRCA1 promotes homologous recombination, a less error-prone repair process.

BRCA1 and Homology Directed DNA Repair

• BRCA1 acts within a complex crucial for homologous recombination.
• Resection of one DNA strand is necessary for homologous recombination.
• BRCA1's exonuclease activity is required for resection.
• If BRCA1 is damaged, non-homologous recombination may occur, leading to mutations.

BRCA1 and BARD1

• BRCA1 and BARD1 form a heterodimer with E3 ubiquitin ligase activity.
• The complex activates and recruits proteins to repair DNA lesions.
• BRCA1 regulates the G2/M checkpoint by activating Chk1 kinase and excluding CDC25 from the nucleus.

BRCA2

• Located on chromosome 13q12-13.
• Relatively large gene, widely expressed.
• Mutations in BRCA2 increase breast cancer risk in males to 5% (x200 that of the general population).
• 14% of male breast cancers are derived from BRCA2 mutations.
• Analysis of large families indicates a 70% risk by age 70.
• Other tumors in BRCA2 families include prostate, pancreas, and lung.

BRCA2 Structure and Function

• Less diverse than BRCA1.
• Transcriptional activation region.
• Multiple sites bind to Rad51.
• Nuclear localisation signal.
• BRCA2 helps BRCA1 carry Rad51.

Roles for BRCA2

• Disruption of BRCA1 and 2 leads to similar phenotypes.
• BRCA2 is necessary for the repair of DSBs by gene conversion.
• BRCA2 binds tightly to Rad51 via the BRC region, indicating a direct role in recombination repair.

BRCA2 and Rad52 in Homologous Recombination

• DNA damage/replication arrest causes DSBs.
• DSBs activate DNA damage signaling kinases (ATM or ATR).
• Phosphorylated BRCA2 releases Rad52, allowing it to bind to DNA and repair the damage.

Cell Cycle and Checkpoint

• Checkpoint arrest following damage is less affected by the disruption of BRCA2 than 1.
• BRCA1 may link BRCA2 DNA repair functions to the pathways that signal incomplete replication or damage.
• BRCA2 may play a role in the repair process by loading Rad51 onto BRCA1.

Mutations and Allele Penetrance

• Penetrance: the ability of a mutation to cause clinical disease in an individual carrying a specific allele.

Non-BRCA Derived Tumors

• Rare familial conditions that result in breast cancer include Fanconi Anemia and Ataxia Telangectasia (AT).
• BRCA type tumors are recognizable due to specific phenotypes, including basal tumors, negative EGFR expression, and lymphocytic infiltration.

Therapy and Treatment

• Surgery, radiotherapy, chemotherapy, and hormonal therapy (anti-oestrogen therapy) are treatment options.
• Herceptin targets the ERBB2 receptor, effective in 30% of early-stage breast cancer.
• Hormone resistance can be acquired or intrinsic.

Hormone Treatment

• 75% of sporadic tumors are Oestrogen receptor (ER) positive.
• Tamoxifen is an oestrogen agonist, effective in 70% of ER-positive and/or progesterone-positive tumors.
• However, 30-50% relapse, and tamoxifen can only be taken for 5 years.

Hormone Resistance

• Intrinsic resistance: tumors that do not express receptors will be resistant.
• Acquired resistance: tumors that stop expressing the receptor and grow in the absence of oestrogen.

This quiz covers the relationship between family history and breast cancer risk, including the role of BRCA1 gene mutations and their impact on genomic integrity.