In the Sept. 24 issue of the journal, Nature Cell Biology, they assign roles to a number
of genes and proteins thought to play a part in breast cancer cell survival, and in the process, have identified potential
molecular drug targets
“It's a very complex
story, but we have been able to bring together a number of basic discoveries from different fields of research to work out
the basic mechanism by which estrogen can exert a pro-life effect on cancer cells," said the study's lead author, Edward T.
H. Yeh, M.D., professor and chair of The University of Texas M. D. Anderson's Department of Cardiology.
Along the way, the researchers have provided some novel insights. One is that they have
provided a role for breast cancer-associated protein 3 (BCA3), which had been recently found to be over-expressed in both
breast and prostate cancers. Yeh and his team show that this protein, by itself, doesn't have any relationship to the cancer,
but when modified by the protein NEDD8, can act like a tumor suppressor.
The researchers also found that SIRT1, a key protein involved in this molecular pathway,
is a member of a family of proteins responsible for prolonging life span in both yeast and worms. "The fact that these molecules,
which maintain life span in other species, has been found to be involved in suppressing cancer development seems important
to us," Yeh said. "The reason people live longer is that they don't develop cancer as readily."
Players in this newly defined pathway are:
- BCA3, which had no known function.
- NEDD8, a protein that can bind to other proteins and alter their function.
- SENP8, a protease (enzyme) that can break bonds between other molecules.
- NFkB (Nuclear Factor kappa B), a family of proteins that turn on genes involved
in cell death (apoptosis) and cell proliferation. When over-expressed, NFkB can protect cells from undergoing apoptosis, and
in general, the more NFkB is expressed, the more resistant the cell is to apoptosis.
- Estrogen, a hormone that acts as growth fuel for about 70 percent of breast
Researchers are interested in ways that cells can efficiently turn genes on or off, and
one of the newest mechanisms is dubbed "NEDDylation," which Yeh helped to find 10 years ago. This process requires multiple
enzymes to attach NEDD8 to other proteins.
To find proteins that can be altered by NEDD8, the four-member research team used yeast
as their experimental platform, and SENP8 as a tool. This enzyme is known to be able to separate NEDD8 from the proteins it
binds to. In this way, they could use SNEP8 "as bait" to fish for protein complexes held together by NEDD8.
They first found that BCA3 binds to SENP8 and was modified byNEDD8, and then discovered
that this complex affects NFkB signaling. It does this by binding on to p65, one of the two proteins that make up NFkB proteins,
the researchers say. "NEDD8 modified BCA3 regulates the activity of NFkB, but BCA3 alone does not have any impact on NFkB,"
Then they looked at how this NEDDylation further works to suppress the ability of NFkB
to transcribe (activate) other genes. Here the investigators found SITR1, the molecule known to prolong life span in several
other species. SITR1 is a histone deacetylase, a protein that blocks transcription factors from regulating genes. "When NEDD8
modified BCA3, it binds to p65 and recruits SITR1 to suppress NFkB-mediated transcription," Yeh said.
Finally, the researchers discovered that estrogen blocks NEDD8 from modifying BCA3, a
finding which goes some way to "explaining estrogen's pro-life effect in breast cancer cells," Yeh says. "Estrogen could enhance
the survival of breast cancer cells by silencing BCA3, through eliminating its hold on NFkB transcription."
Now that this cancer-promoting molecular pathway has been described, Yeh says it might
be possible to interfere with a number of the players to inhibit cancer growth. "NEDD8 is key," he said. "It may be possible
to design drugs that block the removal of NEDD8 from BCA3." By increasing the amount of NEDD8-modified BCA3, there will be
a corresponding decrease in the level of NFkB and the cancer cells will be more sensitive to chemotherapy, Yeh says.
"There is a lot we need to sort out, of course, but this is a model of how estrogen may
function to promote growth in breast cancer that we can all now work from," Yeh says.
Source: University of Texas M. D. Anderson Cancer Center
More on the genetics of breast cancer and
estrogen receptors--a complex story
The BRCA2 protein binds to and regulates
the protein produced by the RAD51 gene to fix breaks in DNA. These breaks can be caused by natural and medical radiation
or other environmental exposures, but also occur when chromosomes exchange genetic material during a special type of cell
division that creates sperm and eggs (meiosis). The BRCA1 protein also interacts with the RAD51 protein. By repairing DNA, these three
proteins play a role in maintaining the stability of the human genome and prevent dangerous gene rearrangements that can lead to hematologic cancers.
Certain variations of the BRCA2 gene cause
an increased risk for breast cancer. Researchers have identified hundreds of mutations in the BRCA2 gene, many of which
cause an increased risk of cancer. BRCA2 mutations are usually insertions or deletions of a small number of DNA base pairs
(the building material of chromosomes) in the gene. As a result of these mutations, the protein product of the BRCA2 gene
is abnormal and does not function properly. Researchers believe that the defective BRCA2 protein is unable to help fix mutations
that occur in other genes. As a result, mutations build up and can cause cells to divide in an uncontrolled way and form a
People who have two mutated copies of the
BRCA2 gene have one type of Fanconi anemia. This condition is caused by extremely reduced levels of the BRCA2 protein in cells,
which allows the accumulation of damaged DNA. Patients with Fanconi anemia are
prone to several types of leukemia (a type of blood cell cancer); solid tumors, particularly of the head, neck, skin, and
reproductive organs; and bone marrow suppression (reduced blood cell production that leads to anemia). A pathogenic mutation almost anywhere in a model pathway for DNA double strand break repair containing BRCA1 and BRCA2 greatly increases the risks for a subgroup
of lymphomas and leukemia.
In addition to breast cancer in men and
women, mutations in BRCA2 also lead to an increased risk of ovarian, Fallopian tube, prostate, and pancreatic cancers, as well as malignant melanoma. In some studies, mutations in the central part of the gene have been associated with
a higher risk of ovarian cancer and a lower risk of prostate cancer than mutations in other parts of the gene. Several other types of cancer have also
been seen in certain families with BRCA2 mutations.
Certain variations of the BRCA1
gene lead to an increased risk for breast cancer. Researchers have identified hundreds of mutations in the BRCA1 gene, many of which are associated with an increased risk of cancer.
Women who have an abnormal BRCA1 or BRCA2 gene have up to an 85% risk of developing breast cancer by age 70; increased risk of developing ovarian cancer is
about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations.
Over 85 distinct BRCA1 mutations and a growing
list of BRCA2 mutations have been identified, with the majority resulting in protein truncation5. A specific
BRCA1 mutation, 185delAG, has a reported increased carrier frequency of approximately 0.9% in the Ashkenazi Jewish
population6, but is also found in rare non-Jewish patients with a different haplotype7. The 6174delT mutation in BRCA2 was recently identified as a frequent mutation in 8 out of 107 Ashkenazi
Jewish women diagnosed with breast cancer by age 50 (ref. 8), as well as in three Ashkenazi male breast cancer patients9.
…. BRCA1 mutation screening on approximately 3,000 Ashkenazi Jewish samples determined a carrier frequency of
1.09% for the 185delAG mutation and 0.13% for the 5382insC mutation. BRCA2 analysis on 3,085 individuals from the same population
showed a carrier frequency of 1.52% for the 6174delT mutation. This expanded population-based study confirms that the BRCA1
185delAG mutation and the BRCA2 6174delT mutation constitute the two most frequent mutation alleles predisposing to
hereditary breast cancer among the Ashkenazim, and suggests a relatively lower penetrance for the 6174delT mutation in BRCA2.
Since BRCA1, the first major gene responsible
for inherited breast cancer, was cloned1, more than 50 unique mutations have been detected in the germline of individuals
with breast and ovarian cancer1-10. In high-risk pedigrees, female carriers of BRCA1 mutations have an 80−90%
lifetime risk of breast cancer11, and a 40−50% risk of ovarian cancer12. However, the mutation
status of individuals unselected for breast or ovarian cancer has not been determined, and it is not known whether mutations
in such individuals confer the same risk of cancer as in individuals from the high-risk families studied so far. Following
the finding of a 185delAG frameshift mutation in several Ashkenazi Jewish breast/ovarian families8,9,13, we have
determined the frequency of this mutation in 858 Ashkenazim seeking genetic testing for conditions unrelated to cancer, and
in 815 reference individuals not selected for ethnic origin. We observed the 185delAG mutation in 0.9% of Ashkenazim (95%
confidence limit, 0.4%−1.8%) and in none of the reference samples. Our results suggest that one in a hundred women of
Ashkenazi descent may be at especially high risk of developing breast and/or ovarian cancer.
There was a high frequency (10/22; [45%]) of germ-line mutations in Ashkenazi
women with ovarian cancer, even in those with minimal or no family history (7/18 [39%]). In high-risk Ashkenazi families,
a founder mutation was found in 59% (25/42). (Thus not
all mutations are significant, since some families have the mutation with a normal history of breast cancer, since the worst
of mutation confer a 905 RISK.)
Frequency and Carrier Risk Associated with
Common BRCA1 and BRCA2 Mutations in Ashkenazi Jewish Breast Cancer Patients
The American Journal of Human Genetics,
Volume 63, Issue 1, Pages 45-51
F. Fodor, A. Weston, I. Bleiweiss, L. McCurdy, M. Walsh,
P. Tartter, S. Brower, C. Eng
risk for breast cancer in Ashkenazi Jewish carriers of the BRCA1 185delAG or BRCA2 6174delT mutations was calculated to be
36%, approximately three times the overall risk for the general population (relative risk 2.9, 95% CI 1.5–5.8).