By Janet Soper

and its Effects in Breast Cancer and

Ovarian Cancer

Breast Cancer 211,300 new cases of

invasive breast cancer in women in 2003

40,200 deaths from breast cancer in 2003

Most frequently diagnosed non-skin cancer in women

Second among cancer deaths in women

www.dressdownday.ca/

Genetically Predisposed

90% of hereditary breast cancers have a mutation in BRCA1 or BRCA2

5% of all breast cancers show a mutation in BRCA1 or BRCA2

https://courses.stu.qmul.ac.uk/smd/kb/humandevelopment/stage2/lectures/cancergenes/brca-1/brca-1.gif

Specifically, BRCA1 confers…

Risk for ovarian cancer as well as breast cancer

Earlier age of onset 80% lifetime risk of cancer- high penetrance Distinct tumors from BRCA2 mutations:

invasive, high grade, lymphocyte infiltration

http://www.baylorcme.org/breastcancer/presentations/plon/presentation_text.html

What is BRCA 1? Cloned in 1994 through genetic

linkage to be on chromosome 17 Expressed in most proliferating cells

www.bmm.icnet.uk/ mainimage.html

http://www.genomenewsnetwork.org/whats_a_genome/Chp1_2_1.shtml

What does BRCA1 do? Multitude of roles

have been proposed: – DNA replication– cell cycle checkpoint

control– DNA repair– regulation of

transcription– protein ubiquitination– apoptosis– chromatin remodeling

www-ermm.cbcu.cam.ac.uk/ 01003155h.htm

In knockout mice… …null for both BRCA1 and BRCA2, embryos died

early in development showed high levels of cell cycle inhibitor p21 radiation sensitivity and measurable drop in rate

of homologous recombination

http://healthsciences.columbia.edu/news/journal/images/psjr_170108.gif

Just in the mammary glands

When BRCA1 was knocked out in just the mammary glands of mice, tumors developed.

When p53 was also mutated, there were even more tumors.

Most tumors in breast and ovarian cancer(90%) have inactivated p53.

www.nih.gov/news/pr/ apr99/niddk-29.htm

Homologous Recombination

Repair of a double strand DNA damage by breakage of two homologous DNA molecules and strand exchange

http://www.onk.ns.ac.yu/Archive/Vol11/News-Scheme1.jpg

In Cancer

Tumor suppressor gene One copy inherited, the second by LOH Heterozygosity is not enough to cause

problems with DSB repair in mutations found thus far

Why only in breast and ovarian cancer?– These areas of proliferation naturally incur the

most DNA damage so require the most homologous recombination

– Expression increases during pregnancy and lactation, increasing the risk

Mutations

Primarily missense, nonsense, and splice-site mutations of single amino acids in one of its binding domains

www.baylorcme.org/.../thumbnails/ plon_026.gif

C-terminus

Two BRCT motifs necessary for protein-protein binding

Truncated by insertion or creation of a stop codon= cancer

BACH1 has been associated with this domain

gloverlab.biochem.ualberta.ca/ structures.html

BACH1

BRCA1-associated c-terminal helicase BRCA1 regulates the cellular location

of BACH1 Over-expression of mutated BACH1

decreases DNA repair Over-expression of mutated BACH1

with an additional mutation in the BRCA1 binding domain rescues

N-terminus

Ring finger domain for protein-protein interaction and E3-ubiquitin ligase activity

Mutation=cancer and radiation sensitivity

Ubiquitination must be important to DNA repair and BRCA1 function http://

www.hosppract.com/genetics/9710gen.htm

BARD1 and BAP1 Binding to BARD1

(BRCA1-associated RING domain protein) increases the ubiquitination function of BRCA1

Also interacts with BAP1, a ubiquitin hydrolase

http://www.hosppract.com/genetics/9710gen.htm

Ubiqui-WHAT??

So it can prevent or promote ubiquitin mediated protein degradation

May ubiquintinate each other FANCD2

– mono-ubiquitinated in response to DNA damage

– mutation in this leads to radiation sensitivity as well

http://www.the-scientist.com/images/yr2003/feb10/brca.gif

How does this cause Cancer?

Resembles p53, which is mutated in most cancers

Makes DNA maintenance less secure, allowing more flaws which can be tumorigenic

carper.senate.gov/ spotlight-breastcancer.html

SourcesBrody, Lawrence C. and Biesecker, Barbara B. “Breast Cancer: The

High-Risk Mutations”.

http://www.hosppract.com/genetics/9710gen.htm

Cancer Facts and Figures 2003, American Cancer Society

Liu, Yilun and West, Stephen. (2001). “Distinct Functions of BRCA1 and BRCA2 in double strand break”. http://breastcancer.com/content/4/1/009

Powell, Simon N. and Kachnic, Lisa A. (2003). “Roles of BRCA1 and BRCA2 in homologous recombination, DNA replication fidelity and the cellular response to ionizing radiation”. Oncogene, 22, 57845791.