Breast genetics

Question 1

Normal breast development

Answer 1

Breast epithelial cells undergo repeated rounds of regulated, hormone-dependent proliferation and involution at different stages of the life cycle
- This process requires that adult cells maintain the capacity for proliferation

Question 2

Maintain capacity for proliferation

Answer 2

adult tissue contains stem cells which provide capacity –> maintain signaling pathways leading to proliferation
NORMAL - takes place by ordered progression along pathway
DYSREGULATION - messing up pathway leads to cancer

Question 3

2 signaling pathways

Answer 3

1. Estrogen/estrogen receptor alpha (E2/ER)

2. EGF/EGFR family

Question 4

Processes affecting development of breast cancer

Answer 4

Initiating event - germline mutation or somatic mutation
Development of tumor - series of somatic mutations (need further mutations)
Host factors - diet, hormone, immune response

Question 5

Germline mutations

Answer 5

contribute to initiation

- 5-10% of breast cancers are due to inherited mutations

Question 6

BRCA 1 and 2

Answer 6

most prevalent breast cancer genetic susceptibility factors

• inherited via autosomal dominance
• BRCA 1 is often inactivated in sporadic forms by promoter methylation (epigenetics)

Question 7

Why does BRCA 1 and 2 inactivation increase susceptibility?

Answer 7

1. essential components of homologous recombination arm of DNA repair machinery –> repairs ds DNA breaks
   - failure to repair leads to susceptibility –> leads to opportunity for accumulation of somatic mutations
2. BRCA 1 is required for differentiation of luminal progentior stage –> accumulate of luminal progenitor cells –> the progenitor cells are dangerous (no receptors for target drugs)

Question 8

Clinical implications of BRCA 1 and 2

Answer 8

genetic testing –> identification of functionally significant deletions/mutations

• additional tests can detect more complicated stuff
• this is feasible –> but hard to interpret

Question 9

Sporadic Breast Cancer

Answer 9

90% of breast cancer

• oncogenesis initiated by somatic genetic change –> likely the driving force as well
• occurs in somatic cell -> not germline

Question 10

Metastasis gene signature

Answer 10

gene expression data from each tumor were compared to clinical outcome data –> gene expression signature that correlated with relapse/metastasis was identified
- could predict outcome of tumor based on gene expression pattern

Question 11

Clinically relevant subtypes

Answer 11

gene expression analysis ID 5 subtypes of distinct gene expression patterns –> reflects different cells of origin
- could predict prognosis and initiate different therapies

Question 12

2 most prevalent subtypes

Answer 12

ER alpha (+)
Her2/neu (+)

Question 13

ER (+) breast cancers

Answer 13

E2/ER signaling is implicated in breast cancer

• breast tissue undergoes repeated rounds of proliferation drive by estrogen (estrogen promotes transcription of cyclin D1)
• many factors that increase risk of breast cancer increase lifetime exposure to estrogen
• treatments to block ER signaling are effective

Question 14

FOXA1

Answer 14

pioneer transcription factor
- can bind closed chromatin –> opens it up and allows ER access to binding site –> cyclin D1 and dysregulation of proliferation

Question 15

Tamoxifen

Answer 15

used to block E2/ER signaling in breast cancer

• ER antagonist in breast tissue –> inhibits transcription
• tamoxifen bind to ER favors interaction with co-repressors, not activators

Question 16

Aromatase inhibitors

Answer 16

block synthesis of estrogen in non-ovarian tissues

- does not effect estrogen receptor

Question 17

HER2/neu overexpressing breast cancers

Answer 17

member of EGF receptor family –> tyrosine kinases

• generally ER negative and more aggressive
• overexpression occurs by genetic amplification
• doesn’t require ligand binding for dimerization (can occur by mass action)

Question 18

Trastuzumab

Answer 18

monoclonal antibody –> binds extracellular domain of HER2 -> blocks activity of HER2 homodimers

Question 19

Lapatinib

Answer 19

small molecule inhibitor –> binds and blocks kinase active site -> blocks HER2 heterodimer activity