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Cancer Biology > Breast Cancer > Flashcards

Breast Cancer Flashcards

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AP® Biology flashcards Biology 101 flashcards
1
Q

What term describes cancers that develop within the lobules that supply the ducts with milk?

A

Lobular carcinomas

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2
Q

What does the BRCA1/BARD1 dimer interact with?

A

RNA Pol 2 At a double-strand break, the transcription complex goes no further. Transcription is blocked, mRNA is no longer made. BRCA1 and BARD1 ubiquitinate the RNA pol 2 enzyme- target it for degradation. BRCA1 becomes bound to the branched DNA directly. BRCA1 recruits the DNA repair complex and repair the double strand region allowing RNA to be synthesised.

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3
Q

What treatments are available to combat breast cancer?

A

Surgery - lumpectomy, mastectomy, lymph node dissection followed by radiotherapy Radiotherapy Chemotherapy Hormonal Therapy (anti-oestrogen therapy) - for hormone receptor positive breast cancers Herceptin

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4
Q

Can mutations in BRCA2 lead to male breast cancer?

A

Yes

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5
Q

What is cdc2’s role in the cell cycle?

A

It controls the transition from G2 to M.

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6
Q

If BRCA2 is mutated in males what is the increased likelihood of breast cancer compared to the general population?

A

200x

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7
Q

How can BRCA1 interact with BRCA2 to repair DNA?

A

BRCA1 may link BRCA2 DNA repair functions to the pathways that signal incomplete DNA replication or DNA damage. BRCA2 may play a role in the repair process by loading Rad51 onto DNA.

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8
Q

Is BRCA1 essential for human survival?

A

No, but it is for mice.

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9
Q

What does over expression of ERBB2 correlate with?

A

Over expression of ERRB2 correlates with a lack of response to endocrine therapies and chemotherapy for breast cancer.

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10
Q

What do the drugs herceptin and trastuzumab do?

A

They block the ERBB2 receptor and ‘flag’ the immune system.

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11
Q

What does herceptin target?

A

Herceptin is a breast cancer drug It targets a member of the epidermal growth factor receptor family - ERBB2 (HER-2) Amplification of ERBB2 occurs in ~30% of early stage breast cancer (not common in BRCA1/2) Over expression of ERRB2 correlates with lack of response to endocrine therapies and chemotherapy.

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12
Q

How does BRCA1 act in a caretaker role?

A

BRCA1 promotes homologous recombination and limits mutagenic non-homologous repair processes.

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13
Q

Is BRCA1 essential for mouse survival?

A

Yes, this makes studying its action difficult.

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14
Q

What inactive allele can inhibit the effectiveness of tamoxifen?

A

An inactive allele of cytochrome p450 2D6 prevent the conversion of tamoxifen to its active state. 8% of caucasian women carry this inactive allele.

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15
Q

How does BRCA1 interact with Wee1?

A

BRCA1 indirectly regulates the expression of Wee1 kinase, which inhibits Cdc2/cyclinB kinase.

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16
Q

How do ATM and ATR interact with BRCA2?

A

ATM and ATR, the DNA-damage signalling kinases, phosphorylate BRCA2 which allows it to release Rad51 and repair the DNA damage.

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17
Q

What role does BRCA1 have?

A

It is important to repair damaged DNA or destroy cells if DNA is irreparable.

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18
Q

How does BRCA2 act as a shuttle?

A

Inactive BRCA2 is bound to Rad51. When activated it releases Rad51 which can bind to DSBs and initiate homologous recombination. BRCA2 becomes inactivated when it releases Rad51. It can then bind Rad51 again when it has repaired the DSBs.

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19
Q

Why is the induction of p27 by herceptin important?

A

p27 is an enzyme inhibitor Its activation results in the inactivation of cell dependent kinases and halts cell cycle progression at G1.

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20
Q

How can caffeine affect ATM/ATR?

A

Caffeine inhibits ATM/ATR resulting the system being unable to recognise DNA damage.

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21
Q

What type of condition is Falcon Anaemia?

A

Fanconi Anaemia is an autosomal recessive familial condition that causes congenital abnormalities, defective haematopoiesis, high risk of AML (acute myeloid leukaemia) and other tumours. Affected patients exhibit chromosomal instability.

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22
Q

What did the sequencing of 100 breast cancers discover?

A

The sequences from 100 breast tumours were compared with somatic tissue to identify tumour specific mutations. 9, previously unidentified ‘driver’ genes were found.

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23
Q

Does BRCA2 bind to Rad51?

A

Yes, BRCA2 binds tightly to Rad51 via the BRC region, this indicates it may have a more direct role in recombination repair.

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24
Q

Where on the chromosome is BRCA2 located?

A

BRCA2 is located on chromosome 13q12-13.§

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25
Q

What is penetrance?

A

Penetrance is the ability of a specific mutation to induce clinical disease in an individual carrying a specific allele.

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26
Q

What percentage of sporadic breast tumours are oestrogen receptor (ER) positive?

A

75%

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27
Q

When ATM or ATR phosphorylates BRCA2 what occurs?

A

Phosphorylation of BRCA2 by the DNA-damage signalling kinases ATM and ATR allows BRCA2 to release Rad51 and repair the DNA damage.

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28
Q

What is the cost for one course of herceptin treatment?

A

£20,000

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29
Q

Why, if BRCA1 is important to repair DS breaks do mutations arises specifically in breast/ovary tissue?

A

Potentially due to hormonal growth during the menstrual cycle that leads to oxidative DNA damage. This oxidative damage leads to increased replication stress and thus DSBs.

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30
Q

Does disruption of BRCA2 interrupt the cell cycle?

A

No, cell checkpoint arrest following DNA damage is less affected by the disruption of BRCA2 than it is by the disruption of BRCA1.

31
Q

How does UCN-01 affect the cell cycle?

A

UCN-01 block Chk1 activity.

UCN-01 is a cyclin dependent kinase that has antiproliferative effects.

32
Q

What is the mode of action for herceptin?

A

Perception down regulates ERBB2 (Her-2) receptor resulting in decreased receptor availability Inhibition of HER family dimerisation blocks signalling Inhibition of the Pi3K/AKT pathway and MAPKs Induction of p27 with G1 arrest Antibody-dependent cell-mediated cytotoxicity

33
Q

Where on the chromosome is BRCA1 located?

A

Chromosome 17 at region 2, band 1

34
Q

How many distinct germline mutations are there in BRCA1/2 in the general population?

A

>1500

35
Q

What term describes breast cancers that develop within the cells of the milk duct lining?

A

Ductal carcinomas

36
Q

Do BRCA1 and BRCA2 interact with each other?

A

Yes, they have physical interactions.

37
Q

What is Rad51?

A

Rad51 is a gene that codes for a protein that assist with the repair of double strand breaks. BRCA1 co-localises at these sites. BRCA1-/- and Rad51-/- mice have similar phenotypes (embryonic cells)

38
Q

If there is a mutation in BRCA1 how is its caretaker role inhibited?

A

BRCA1 promotes highly accurate repair via homologous recombination and limits mutagenic action in non homologous repair. Its inactivation can lead to genetic instabilities that leads to an increase in all mutations in all genes.

39
Q

What type of gene is BRCA1?

A

A tumour suppressor gene

40
Q

How does knocking out BRCA1 or BRCA1 mutation lead to problems with the exonuclease activity of the complex?

A

BRCA1 has a role in ‘chewing back’ the damaged DNA exposing free ends for strand invasion. BRCA1 is thought to affect the exonuclease activity of the complex. A BRCA1 knockout cell line utilises the non-homologous repair pathway instead of homologous recombination. This is because the strands are not available and there is no exonuclease activity.

41
Q

What drugs can be used to block the ERRB2 receptor?

A

Monoclonal antibodies - Trastuzumab or Herceptin

42
Q

What is the risk of heart disease/stroke for patients that are treated with herceptin?

A

~5%

43
Q

What mutation causes Ataxia Telangiectasia?

A

AT gene encodes a 12kb transcript that maps to chromosome 11q. The protein product is involved in DNA repair.

44
Q

How can BRCA1 influence cdc25?

A

BRCA1 can alter the localisation of cdc25. Its activity results in the exclusion of cdc25 from the nucleus and blocks the cell cycle. cdc25 instead located in nucleus, cells will not divide until DNA is repaired.

45
Q

What drug can be used in hormone treatment against breast cancer?

A

Tamoxifen - Oestrogen antagonist - Effective in 70% of ER positive tumours - 40-50% of patients relapse - Can only be tolerated for 5 years

46
Q

How do repair mechanisms differ between cells that are normal and those that have BRCA mutations?

A

In a normal cell DNA damage is repaired through homologous recombination with high accuracy leading to genomic stability. In BRCA deficient cells, they are unable to repair via homologous recombination so it uses alternative repair pathways, this leads to genomic instability.

47
Q

How does BRCA1 interact with BASC?

A

BASC (BRCA1 associated genome surveillance complex) BRCA1 sits at the hub of a number of tumour suppressor pathways. Inactivation of BASC may be an important event in tumourigenesis.

48
Q

What is cdc25’s role in the cell cycle?

A

It promotes the transition from G2 to M.

49
Q

What non-BRCA derived tumours are there that show familial inheritance?

A

Falcon Anaemia Ataxia Telangectasia

50
Q

How does BRCA1 interact with RNA pol II?

A

BRCA1 functions as a dimer with BARD1. RNA polymerase II travels along the DNA, synthesising an mRNA. It cannot proceed through regions of DNA damage. When the transcription complex reaches a lesion in the dsDNA template transcription is blocked. The block is recognised by BRCA1-BARD1. BRCA1-BARD1 ring finger mediated ubiquitination of RNA pol II. RNA pol II is then removed and degraded. BRCA1 becomes bound to the branched DNA, marking the damaged region. The DSB is repaired resulting in functional DNA.

51
Q

How do BRCA1 and BARD1 interact with each other?

A

Via their ring domains

52
Q

How does BRCA1 interact with Chk1?

A

BRCA1 activates Chk1 kinase and regulates DNA damaged-induced G2/M arrest.

53
Q

How many exons does BRCA2 have?

A

27 exons, 3418 amino acids.

54
Q

What occurs when perception inhibits the HER family dimerisation?

A

Signalling is blocked The Pi3K/AKT pathway and MAPKs are inhibited p27 is induced and G1 arrested (division stops) Antibody-dependent cell-mediated cytotoxicity is induced.

55
Q

What is BARD1?

A

BARD1 forms a heterodimer with BRCA1 This heterodimer had significant E3 ubiquitin ligase activity.

56
Q

If BRCA2 is mutated how is Rad51 affected?

A

BRCA2 is directly coupled to Rad51. If mutated it will not be able to bind to Rad51 and thus will not be localised at regions of DNA damage.

57
Q

How do cdc2, wee1 and cdc25 become linked to DNA damage?

A

DNA damage activates the molecules ATM and ATR which in turn activate Chk2 and Chk1.

These molecules compete with one another to either up regulate wee1 (suppress the transition from G2 to M)

OR

If DNA damage isn’t present then up regulate cdc25 allowing progression through the cell cycle.

58
Q

What is the role of wee1 in the cell cycle?

A

It suppresses the transition from G2 to M in the cell cycle.

59
Q

What exon is particularly large in BRCA1 and BRCA2?

A

Exon 11 is very long, only similarity between them. The proteins are not related to each other structurally. Both simply give rise to breast and ovarian cancer.

60
Q

What is the role of p53 in the cell cycle?

A

p53 is a tumour suppressor It can arrest the cell cycle at the G1/S regulation point.

61
Q

What condition is Ataxia Telangiectasia?

A

Ataxia Telangiectasia is a non-BRCA condition that can cause breast tumours. It is autosomal recessive. Individuals are particularly susceptible to double strand break with increased cancer risk and chance of cerebellar ataxia.

62
Q

What similarities are there between the BRCA1 and BRCA2 phenotypes?

A

They amplify c-MYC There are mutations in TP53 Loss of Rad51-focus formation Extreme genomic instability Sensitive to DNA-cross linking agents

63
Q

How many times more common is breast cancer in women than in men?

A

100x

64
Q

How do BRCA1 and cdc25 interact?

A

BRCA1 activity results in the exclusion of cdc25 form the nucleus, this leads to a block in the cell cycle.

65
Q

What is the role of UCN-01?

A

UCN-01 blocks CHK1 activity This inhibits the cell cycle in the presence of DNA damage by blocking cdc25.

66
Q

What issues are there with herceptin treatment?

A

Herceptin, combined with chemotherapy can increase the response to the chemo by 25% - However, the amplification of Her-2 only occurs in 30% of tumours. Other genes are also amplified

67
Q

Why do patients relapse to breast cancer after taking tamoxifen?

A

40-50% of tamoxifen patients relapse Develop intrinsic resistance Anyone who does not express the Erα receptor will be resistant to tamoxifen treatment 8% of caucasian women carry an inactive allele of cytochrome p450 2D6, this cannot convert tamoxifen to its active stage

68
Q

Why is penetrance of BRCA1/2 hard to calculate?

A

There are over 1500 germline mutations.

69
Q

What function does the BARD1 and BRCA1 heterodimer have?

A

E3 ubiquitin ligase activity - It can ubiquitinate and target proteins for degradation

70
Q

What cellular checkpoint does BRCA1 influence?

A

BRCA1 promotes the block of G2/M transition in the presence of DNA damage.

71
Q

What large complex is formed when BRCA1 associated with other tumour suppressors and molecules?

A

BASC BRCA-associated genome surveillance complex BRCA1 associated with other tumour suppressors, DNA damage sensors and signal transducers

72
Q

Which are more severe, BRCA1 or BRCA2 type tumours?

A

BRCA1 tumours are more severe. - Basal, poorly differentiated tumours - Very aggressive - ER-negative (oestrogen receptor) - Can infiltrate lymphocytes

73
Q

When double strand breaks occur what kinases are activated?

A

DSBs activate DNA-damage signalling kinases such as ATM or ATR

74
Q

What is ERRB2?

A

ERRB2 is a member of the epidermal growth factor family and is targeted by HERCEPTIN

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