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Endo/Repro: Week 6 > Scott: Breast Cancer Genetics > Flashcards

Scott: Breast Cancer Genetics Flashcards

1
Q

breast cancer arises from what layer of tissue

A

epithelial layer

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2
Q

inner layer
contains ductal and alveolar cells
contain ERa cells and - cells
progenitor cells

A

luminal layer

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3
Q

outer layer
contains primarily contractile cells
contains stem cells
ALL ERa +

A

myoepithelial layer

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4
Q

how does normal breast development create conditions for development of breast cancer?

A

adult tissue has STEM cells and PROGENITOR cells> maintain signaling therapy> proliferation/capacity to grow thorugh lifespan

Normally: ordered progression along pathway> leads from SC to fully differentiated cells

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5
Q

2 key signaling pathways that play a role in dysregulation

A

estrogen/estrogen receptor a

EGF/EGFR

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6
Q

development of breast cancer requires

A

GENETIC (germline/somatic) and HOST (diet, hormones, IR) factors

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7
Q

accounts for 5-10% of inherited breast cancer mutations

A

germine genetic changes (pts have relatives w/ breastcancer)

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8
Q

Most PREVALENT breast cancer genetic susceptiblity factor that accounts for 20% of FAMILIAL breast cancers

A

BRCA1/2

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9
Q

BRCA1

A

65% breast cancer

40% ovarian cancer (no early dx)

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10
Q

BRCA2

A

40% breast cancer

11% ovarian cancer

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11
Q

inheritance of BRCA

A

AD

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12
Q

how is BRCA1 often INACTIVATED in sporadic tumors

A

promoter methylation (epigenetic mechanism)

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13
Q

ATM
CHEK2
PALB2
BRIP1

A

other mutations in DNA repair gens that can lead to 2-3 fold increased risk

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14
Q

Why does inactivation of BRCA1/2 lead to breast cancer susceptibility?

A

BRCA are needed for DNA repair during homologous recombination

Repair defect in BRCA1/2 mutant cells>
genomic instability>
opportunity of accumulation of somatic cancer causing mutations

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15
Q

recruited as recognition complex after recognition of a break

A

BRCA1

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16
Q

prepairs ends from repair to create a SINGLE stranded end and recruits repair machinery

A

BRCA1

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17
Q

promotes new DNA syntehsis and recruits Rad51 to promote strand invasion

A

BRCA2

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18
Q

leads to luminal progenitor accumulation

A

mut BRCA1–> required for differentaiation

19
Q

why are there limited tx options for BRCA1 tumors?

A

b/c they develop from the luminal progenitor stage they are often TRIPLE NEGATIVE

20
Q

standard test for BRCA1/2 genetic testing

A

full gene seq for pt muations, and insertions/deletions in bRCA1/2

21
Q

accounts for 90% of breast cancers

A

sporadic cancers (somatic mutations)

22
Q

Somatic changes

A

random somatic mutations (microevolution) are inheriited from one cell division to next but it is NOT passed down from parent to child

23
Q

Initiating event in MOST breast cancers and driving force in both familial and sporadic cancers

A

somatic genetic changes

24
Q

oncotype dx

A

gene expression signature correlated w/ level of relapse/mets

25
Q

compares expression pattern in normal vs tumor cells> tumors grouped into similar mRNA expression

A

Microarray

26
Q

why was it important to identify the 5 clinical subtypes?

A

diff subtypes have diff gene expression/cells of origin> diff tx/prognosis

27
Q

high levels of estrogen receptor

best prognosis

A

luminal A= luminal progenitor

28
Q

overexpression of HER2

prognosis improved w/ use of TRASTUZUMAB

A

her 2 amplified= progenitor

29
Q

triple negative
often BRCA1 inactivated by methylation of promoteor
worst prognosis- no targetd therapy

A

basal like tumor

*from earliest luminal progenitor

30
Q

accounts for 65% of breast cancers

A

ER alpha

31
Q

how did they figure out that ER signaling was implicated in breast cancer?

A

blocking ER signaling was HIGHLY effective in treating ER + breast caancer

32
Q

what controls normal proliferation of luminal cells?

A

extracellular estrogen

ER binds ERa>
trxn of paracrine GF>
acts on nearby cells>
proliferation

Cells expressing ER PROLIFERATE while cells taht don’t do NOT

33
Q

how can estrogen exposure increase the risk for cancer in normal tissue?

A

longer exposure> increased risk/opp to make mutations

34
Q

what is the role of ER in ER + breast cancers?

A 
Est>
binds ER>
upregulates FOXA1>
allows increased access of ER to DNA for trxn>
incrased availibility of promoter for cyclin D>
increased trxn of cylcin D>
progression through G1/S checkpoint>
cell proliferation
35
Q

assoc w/ a GOOD prognosis b/c can tx w/ selective SERMS/aromatase inhibitors

A

ER + brast cancer

36
Q

ER antagonist that reduces breast cancer recurrence and mortality

A

Tamoxifen

37
Q

binds to ER and favors interaction w/ co repressors>

BLOCKS ER dep trxn/proliferation

A

tamoxifen

38
Q

blocks synthesis of estrogen in NON ovarian tissues but does NOT affect ER

A

aromatase inhibitors

39
Q

Genomic amplification of TK receptor>

aggressive ER negative tumor

A

ERBB2= E

GF receptor family

40
Q

how is ERBB2 overexpression oncogenic?

A

ERBB2 dimerization>
domain constantly OPEN>
does NOT require ligand binding>
CELL CYCLE PROCEEDS INDEPENDENTLY OF GROWTH FACTORS

41
Q

monoclonal Ab that binds extracellular domain of ERBB2>

blocked activity of homodimers

A

TRastuzumab

42
Q

increases survival in Her2 overexpressing cancers

A

trastuzumab

43
Q

small moleucle inhibitor that BLOCKS kianse active site> EGFR-ERBB2 heterodimer activity

A

Lapatinib

Endo/Repro: Week 6 (8 decks)

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