Breast Cancer Genetics

Question 1

The epithelium consists of luminal cells and myoepithelial cells. Which layer contains the progenitor cells?

Answer 1

the luminal cells

but th emyoepithleial cells also contain stem cells

Question 2

Why is it important that adult breast epithelial cells maintain the capacity for proliferation?

Answer 2

they have to go repeated rounds of regulated, hormone-dependent proliferation and involution at different stages of the life cycle

Question 3

How is that capacity maintained?

Answer 3

the adult tissue contains stem cellsa nd progenitor cells which allows for proliferation throughout the lifetime

Question 4

WHat are the two main key signalling pathways essential for normal breast development?

Answer 4

estrogen on ERalpha

EGF on the EGFR family

Question 5

Are initiating mutations enough to cause breast cancer?

Answer 5

no - you need subsequent mutations (all somatic typically)

Question 6

Germline genetic changes can contribute to breast cancer initiation. Familial aggregations studies suggest that ___% are due to inherited breast cancer mutations.

Answer 6

5-10%

Question 7

What is the most common gene mutation in familial breast cancer?

Answer 7

BRCA1 and BRCA2

Question 8

BrCA1 breast CA risk =?

ovarian CA risk = ?

Answer 8

65%

40%

Question 9

How about for BRCA2?

Answer 9

breast cancer - 40%

ovarian - 11%

Question 10

Inheritence of susceptibility is antosomal -_____

Answer 10

dominant

Question 11

BRCA1 is often inactivated in sporadic tumors by what?

Answer 11

epigenetic mechanisms

so you don’t have to have the germline mutatuion

Question 12

What does BRCA do under normal contision?

Answer 12

they are essential parts of the homologous recombination machinery to repair double-straded DNA breaks

failure of repair leads to genomic instability, which leads to further ongoenic mutations to arise.

Question 13

So do the BRCA mutations cause cancer in and of themselves?

Answer 13

no - they create conditions that allow for more mutations that then cause the cancer

Question 14

Why does BRCA1 have a little higher risk? And why does this limit treatment options?

Answer 14

BRCA1 is also important for differentiation at the luminal progenitor stage

this is a problem in mutation because those cells, if they do become cancerous, can be especially dangerous because they don’t have any receptors at that point - harder to treat

Question 15

What type of sporadic tumors will resemble those of BRCA1 mutations?

Answer 15

basal-like sporadic tumors

often triple negative as well, making them harder to treat

Question 16

How many different varians have been identified in BRCA1?

Answer 16

over 1500!

Question 17

BRCA1/2 account for only 40% of familial breast cancer cases. What are some other genetic issues that can lead to problems?

Answer 17

ATM
CHEK2
NBS1
RAD51
PTEN
and lots more...but are not in the standard tests because their contribution is so small

Question 18

How did we identify molecules subtypes of breast cancer?

Answer 18

microarray analysis to compare gene expression between normal and tumor tissues

allowed us to group tumors based on similar mRNA expression patterns

Question 19

Connecting this microarray analysis to clinical outcome data allowed for development of what?

Answer 19

allowed us to develop oncotype Dx to determine how a tumor will act based on its genetics

Question 20

What are the 5 subtypes of breast cancer based on these results?

Answer 20

claudin low (normal breast-like - arise from stem cells)

basal - earliest luminal progenitor

her2-amplified

Luminal B

Luminal A

Question 21

Which subtype has the best prognosis?

Answer 21

luminal A - because it has the highest levels of estrogen receptor (developed from late luminal progenitor) and can be treated with Tamoxifen or aromatase inhibitors

Question 22

What has the second best prognosis?

Answer 22

her2-amplified, so can be treated with trastuzumab

this actually had one of the worst prognosis before trastuzumab!

Question 23

What percentage of breast cancers are ERalpha positive?

Answer 23

65%

Question 24

What percentage have Her2 overexpression?

Answer 24

25%

Question 25

Describe estrogen receptor signaling under normal conditions?

Answer 25

steroid hormone that acts as a transcription factor for genes that promote proliferation and cell survival (growth factors, etc)

Question 26

The ER is expressed in a minority of luminal epithelial cells, but those calls don’t actually proliferate! so how does it promote growth?

Answer 26

it promotes expression of PARACRINE growth factors that will on neighboring cells

Question 27

Describe how ER signalling can change in cancer?

Answer 27

cancers have more cells that are ERalpha positive.

furthermore, estrogen will cause proliferation in both the ER expressing cells and the nearby cells

Question 28

What is the most improtant cell cycle regulator that is promoted by estrogen?

Answer 28

cyclin D1 - so you lose that checkpoint

Question 29

Some tumor cells have dysregulated ER signalling, but the ER receptors are normal. What mutation is going on here?

Answer 29

defect in some other part of the signalling pathway

overexpression of FOXA1

Question 30

Describe what happens with FOXA1.

Answer 30

ER can’t bind to closed chromatin

but FOXA1 can bidnt o closed chromatin at select site and open it to allow for ER binding

one of these sites is the promoter for cyclin D1

Question 31

How does tamoxifen binding to ER block transcription?

Answer 31

Tamoxifen binding favors interactions with co-repressors, not co-activators

Question 32

What are the two other HER2 names?

Answer 32

ERBB2

Neu (the name in mice)

Question 33

ERBB2 is a member of what receptor family?

Answer 33

EGF receptor family

Question 34

Members of the EGF receptor family are what kind of receptors?

Answer 34

tyrosine kinases

Question 35

ERBB2 overexpressing cancers are generally ER ____?

Answer 35

negative

Question 36

Are they more aggressive than ER+ cancers?

Answer 36

yes

Question 37

How does ERBB2 signalling cause cancer?

Answer 37

under normal conditions, when EGF binds the ERBB2, you get dimerization and tyrosine kianse activity leading to cell signaling pathways which promote G1 to S phase progression

with the mutation, the dimerization domain is constitutively open so that you always have tyrosine kinase activity and uncontrolled proliferation

Question 38

What are the two drugs against the ERBB2 receptor?

Answer 38

Trastuzumab (Hercephin)

Lapatinib

Question 39

How do these drugs work differently from each other?

Answer 39

Transtuzumab is against the receptor

Lapatinib blocks the kinase active site of the EGFR-ERBB2 herheterodimer