Cancer (= malignant neoplasm) is a class of diseases in which a group of cells display uncontrolled growth (division

beyond the normal limits), invasion (intrusion on and destruction of adjacent tissues), and sometimes metastasis
(spread to other locations in the body via lymph or blood)

Tumor (= neoplasm) is an abnormal mass of tissue as a result of abnormal proliferation of cells (neoplasia).
Tumor/neoplasm may be benign, pre-malignant or malignant. literally means new growth

neoplasia: a growth disorder characterized by genetic alterations that lead to loss of the normal control mechanisms
that regulate cell growth, morphogenesis and differentiation

neoplasm: an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal
tissues and persists in the same excessive manner after the cessation of the stimuli which evoked the change

Neoplasm = tumor

Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels.
This is distinct from vasculogenesis, which is the de novo formationof endothelial cells from mesoderm cell
precursors. The first vessels in the developing embryo form through vasculogenesis, after which angiogenesis is
responsible for most, if not all, blood vessel growth during development and in disease.

Angiogenesis is a normal and vital process in growth and development, as well as in wound healing[ and in the
formation of granulation tissue. However, it is also a fundamental step in the transition of tumors from a benign
state to a malignant one, leading to the use of angiogenesis inhibitors in the treatment of cancer. The essential
role of angiogenesis in tumor growth was first proposed in 1971 by Judah Folkman, who described tumors as
"hot and bloody.

1. Benign tumor is self-limited and does not invade and metastasize. The term "benign" implies a mild and
nonprogressive disease, and indeed, many kinds of benign tumors are harmless to the health.
2. Pre-malignant tumor (=pre-cancer, carcinoma in situ/CIS) is an early form of carcinoma defined by the
absence of invasion of surrounding tissues. The neoplastic cells proliferate in their normal habitat, hence the
name "in situ" (Latin for "in its place"). Many forms of cancers originate from a CIS lesion
3. Malignant tumor (= cancer) is a type of neoplasm which invade and destroy the surrounding tissue, may
form metastases and eventually kill the host.
 A carcinogen is any substance, radionuclide, or radiation that is an agent directly involved in
causing cancer. This may be due to the ability to damage the genome or to the disruption of
cellular metabolic processes. Several radioactive substances are considered carcinogens, but their
carcinogenic activity is attributed to the radiation, for example gamma rays and alpha particles, which they
emit. Common examples of non-radioactive carcinogens are inhaled asbestos, certain dioxins,
and tobacco smoke. Although the public generally associates carcinogenicity with synthetic chemicals, it is
equally likely to arise in both natural and synthetic substances.[1]Carcinogens are not necessarily
immediately toxic, thus their effect can be insidious

Proto-oncogene: A normal gene which, when altered by mutation, becomes an oncogene that can contribute
to cancer. Proto-oncogenes may have many different functions in the cell. Some proto-oncogenes provide
signals that lead to cell division. Other proto-oncogenes regulate programmed cell death (apoptosis).
The defective versions of proto-oncogenes, known as oncogenes, can cause a cell to divide in an unregulated
manner. This growth can occur in the absence of normal growth signals such as those provided by growth
factors. A key feature of oncogene activity is that a single altered copy leads to unregulated growth

Oncogene: 1. A gene that played a normal role in the cell as a proto-oncogene and that has been
altered by mutation and now may contribute to the growth of a tumor.

Some of the more important oncogenes include:

 ras (a signal transduction molecule),

 myc (a transcription factor), src (a protein tyrosine kinase),

 HER-2/neu, also called erbB-2 (a growth factor receptor),

 hTERT (an enzyme involved in DNA replication), and

 Bcl-2 (a membrane associated protein that prevents apoptosis).

Genes and cancer treatment

Drugs targeting genes or gene mutations

Drugs have been developed that target some of the gene changes in certain cancers. Actually these drugs often
target the protein made by the abnormal gene (and not the gene itself).

For example, HER2/neu is a proto-oncogene in normal cells that helps them grow. It becomes an oncogene when
a cell has too many copies of this gene. When this happens, the cells make too much HER2/neu protein and the
 cancer is said to be HER2 positive. Patients with breast cancer with cells that are HER2 positive do not respond as
well to certain chemotherapy drugs. But newer drugs such as trastuzumab (Herceptin®), lapatinib (Tykerb®), and
several others, have been designed to specifically attack cells that are HER2 positive. These drugs can slow
cancer cell growth and improve outcomes in patients with HER2 positive cancers. Breast cancers are now
routinely tested to see if they are or the HER2 positive to identify which patients will benefit from these drugs.
Other cancers also can be HER2 positive. Anti-HER2 therapy has also helped people with stomach cancer that is
HER2-positive.

In chronic myeloid leukemia (CML), the cancer cells have a gene change called BCR-ABL that makes a type of
protein called a tyrosine kinase. Drugs that target the BCR-ABL protein, such as imatinib (Gleevec®), are often
very effective against CML. They lead to remission of the leukemia in most patients treated in the early stages of
their disease.

Drugs targeting certain mutations are useful in a number of other cancers including acute lymphocytic leukemia,
gastrointestinal stromal tumors, non-small cell lung cancer, a certain kind of non-Hodgkin lymphoma, and
melanoma.

What Causes Swollen Glands?

The most common causes of swollen glands include:

 Bacterial infection such as strep throat or tonsillitis

 Mouth sores or tooth infection
 Viral infection such as mononucleosis or "mono"
 Skin infection
 Ear infection
 Sexually transmitted disease
 Cancers such as leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, and breast cancer
 Immune system disorders such as lupus, rheumatoid arthritis, andHIV infection
 Side effect from a vaccine or from certain medications

Differences between swollen lymph nodes and tumor:

A swollen lymph node can be anything simple like an infection, but it can also be a dangerous and risky
swelling, which can be cancerous.
A tumor is a swollen mass that can be two things: it will not pose any threat if it is benign; it can be
dangerous if it is cancerous.
A tumor can be determined if it is cancerous or not through laboratory test called ‘biopsy’. Your doctor
would be the one to inform you if a lump is a tumor and would have to be biopsied.
A lymph node can swell due to your body’s response to bacteria, fungal, and viral infections.

http://pathmicro.med.sc.edu/lecture/retro.htm

Cancers are the result of a disruption of the normal restraints on cellular proliferation. It is apparent that the
number of ways in which such disruption can occur is strictly limited and there may be as few as forty
cellular genes in which mutation or some other disruption of their expression leads to unrestrained cell
growth.
There are two classes of these genes in which altered expression can lead to loss of growth control:
(a) Those genes that are stimulatory for growth and which cause cancer when hyperactive. Mutations in
these genes will be dominant. These genes are called oncogenes.
(b) Those genes that inhibit cell growth and which cause cancer when they are turned off. Mutations in
these genes will be recessive. These are the anti-oncogenes or tumor-suppressor genes.

Viruses are involved in cancers because they can either carry a copy of one of these genes or can alter
expression of the cell's copy of one of these genes.

CLASSES OF TUMOR VIRUSES

There are two classes of tumor viruses:

 DNA tumor viruses

 RNA tumor viruses, the latter also being referred to as RETROVIRUSES.

We shall see that these two classes have very different ways of reproducing themselves but they often
have one aspect of their life cycle in common: the ability to integrate their own genome into that of the host
cell. Such integration is not, however, a pre-requisite for tumor formation.

TRANSFORMATION AND ONCOGENES

If a virus takes up residence in a cell and alters the properties of that cell, the cell is said to be transformed.
Transformation by a virus is the change in the biological properties of a cell that results from the regulation
of the cell by viral genes and that confer on the infected cells certain properties of neoplasia.

Transformation often includes loss of growth control, anchorage-independent growth, ability to

invade extracellular matrix, dedifferentiation and immortalization. In carcinomas, many epithelial cells
undergo an epithelial-mesenchymal transformation. Transformed cells often exhibit chromosomal
aberrations and the changes seen in transformation often, but not always, result from the integration of the
viral genome into the host cell's chromosomes.

The region of the viral genome (DNA in DNA tumor-viruses or RNA in RNA-tumor viruses) that can cause
a tumor is called an oncogene. This foreign gene can be carried into a cell by the virus and cause the host
cell to take on new properties.

The discovery of viral oncogenes in retroviruses led to the finding that they are not unique to viruses and
homologous genes (called proto-oncogenes) are found in all cells. Indeed, it is likely that the virus picked
up a cellular gene during its evolution and this gene has subsequently become altered. Normally, the
cellular proto-oncogenes are not expressed in a quiescent cell since they are involved in growth (which is
not occurring in most cells of the body) and development; or they are expressed under strict control by the
cell. However, they may become aberrantly expressed when the cell is infected by tumor viruses that do
not themselves carry a viral oncogene. We shall see later how this happens but it is clear that a virus may
cause cancer in two ways: It may carry an oncogene into a cell or it may activate a cellular proto-
oncogene.

The discovery of cellular oncogenes opened the way to the elucidation of mechanisms by which non-virally
induced cancers may be caused. We shall investigate what the protein products of the viral and cellular
oncogenes do in the infected cell and in cells in which cellular proto-oncogenes are expressed. We shall
see that their functions strongly suggest mechanisms by which cells may be transformed to
a neoplastic phenotype. The discovery of cellular oncogenes led to the discovery of another class of
cellular genes, the tumor repressor (suppressor) genes or anti-oncogenes.

Initially, the involvement of viral and cellular oncogenes in tumors caused by retroviruses was much more
apparent than the involvement of the DNA tumor virus oncogenes but the discovery of tumor repressor
genes (as a result of our knowledge of how retroviruses cause cancer) led to the elucidation of the mode of
action of DNA virus oncogenes.

It should be noted that while retroviruses have been instrumental in elucidation of the mechanisms of
oncogenesis, most human cancers are probably not the result of a retroviral infection although retroviruses
are important in cancers in some animals. It is becoming much more apparent that many human tumors
may result from infection by DNA tumor virsues.

DNA TUMOR VIRUSES

DNA tumor viruses have two life-styles:

In permissive cells, all parts of the viral genome are expressed. This leads to viral replication, cell lysis and
cell death

In cells that are non-permissive for replication, viral DNA is usually, but not always, integrated into the cell
chromosomes at random sites. Only part of the viral genome is expressed. This is the early, control
functions (e.g. T antigens) of the virus. Viral structural proteins are not made and no progeny virus is
released.

TUMOR ANTIGENS ARE ONCOGENES

Tumors caused by papilloma virus, adenovirus or polyoma virus contain viral DNA but do not produce
infectious virus. The presence of the virus, however, elicits the formation of antibodies against the tumor
antigens. In the case of adenoviruses, only part of the viral genome is found in the host cell chromosomes
whereas SV40 may integrate part or all of its genome. Whether or not the whole SV40 genome is
integrated, only a part of the genome is transcribed into mRNA and protein and this is the region that
encodes the early functions of the virus replication cycle.

Many DNA viruses have early and late functions. Early functions are the result of the expression of
proteins that prime the cell for virus production and are involved in viral DNA replication. These proteins
are expressed before genome replication and do not usually end up in the mature virus particle. Late
functions are the results of the expression of viral structural proteins that combine to form the mature virus.
They are expressed during and after the process of DNA replication. Since early functions are involved in
the replication of the viral genome, it is not surprising that they can also alter the replication of host cell
DNA.

SV40 expresses two such proteins, the T antigens (large T and small T antigen). The large T antigen acts
as a cis-regulatory element at the level of viral DNA replication by binding to the origin of replication and
stimulating transcription. It can also bind to and modulate the activity of host cell DNA polymerase alpha.

As we shall see later, DNA replication in the cell is controlled by suppressor proteins (the best studied of
which are the retinoblastoma (Rb) and p53 suppressor proteins). SV40 large T antigen can bind directly to
these proteins and inactivate them, thereby inducing the cell to go from Go to S phase. Because polyoma
viruses have a small genome, they rely on many cell functions for DNA replication and it is important that
the virus causes the cell to enter S phase because it creates a suitable environment for viral DNA
replication.

Thus SV40 Large T antigen:

 is necessary for transformation of a cell to the cancerous state

 stimulates the host cell to replicate its DNA
 is found mostly in the nucleus (to which it is directed by its nuclear
localization signal) but a small amount goes to the cell surface (where it is a
tumor-specific transplantation antigen)
 binds to cellular DNA
 binds to p53 protein (see below)

A second T antigen (small T antigen) interacts with a family of cellular phosphatases (called pp2A) which
results in the failure of certain cellular proteins to be phosphorylated, thereby relieving cell cycle arrest.

In mouse polyoma virus, there is also a middle T antigen which can act as an oncogene.

Similarly, in adenovirus-induced tumors, only a part of the viral genome becomes integrated and again it is
the early region genes. This region codes for the E1A and E1B proteins. In papilloma virus-induced tumor,
again, two early genes, E6 and E7, are expressed.

Thus, papilloma, polyoma and adenoviruses seem to cause cell transformation in a similar manner: the
integration of early function genes into the chromosome and the expression of these DNA synthesis-
controlling genes without the production of viral structural proteins. As we shall see later, all three virus
types induce cell proliferation by interacting with tumor suppressor genes.

Two important points that should be emphasized about T antigens of DNA tumor viruses as oncogenes:

 They are true viral genes. There are no cellular homologues in the uninfected cell
 They are necessary in lytic infections because they participate in the control of viral and
cellular DNA transcription

RNA TUMOR VIRUSES (RETROVIRUSES)

Retroviruses are different from DNA tumor viruses in that their genome is RNA but they are similar to many
DNA tumor viruses in that the genome is integrated into host genome.

Since RNA makes up the genome of the mature virus particle, it must be copied to DNA prior to integration
into the host cell chromosome. This life style goes against the central dogma of molecular biology in which
that DNA is copied into RNA.

Retrovirus structure

The outer envelope comes from the host cell plasma membrane
Coat proteins (surface antigens) are encoded by env (envelope) gene and are glycosylated. One primary
gene product is made but this is cleaved so that there are more than one surface glycoprotein in the
mature virus (cleavage is by host enzyme in the Golgi apparatus). The primary protein (before cleavage) is
made on ribosomes attached to the endoplasmic reticulum and is a transmembrane (type 1) protein.

Inside the membrane is an icosahedral capsid containing proteins encoded by the gag gene (Group-
specificAntiGen). Gag- encoded proteins also coat the genomic RNA. Again there is one primary gene
product. This is cleaved by a virally-encoded protease (from the pol gene)

There are two molecules of genomic RNA per virus particle with a 5' cap and a 3' poly A sequence. Thus,
the virus is diploid. The RNA is plus sense (same sense as mRNA).

About 10 copies of reverse transcriptase are present within the mature virus, these are encoded by
the pol gene.

Pol gene codes for several functions (again, as with gag and env, a polyprotein is made that is then cut up)

The pol gene products are:

a) Reverse transcriptase (a polymerase that copies RNA to DNA)

b) Integrase (integrates the viral genome into the host genome)

c) RNase H (cleaves the RNA as the DNA is transcribed so that reverse transcriptase can make the
second complementary strand of DNA)

d) Protease (cleaves the polyproteins translated from mRNAs from the gag gene and the pol gene itself).
This virally encoded protease is the target of a new generation of anti-viral drugs.

INFECTION AND TRANSFORMATION OF A CELL BY A RETROVIRUS

The following stages occur in the infection process:

1) Binding to a specific cell surface receptor

2) Uptake by endocytosis or by direct fusion to the plasma membrane. The virus may require entry into a
low pH endosome before fusion can occur, although some (e.g. HIV) can fuse directly with the plasma
membrane

3) RNA (plus sense) is copied by reverse transcriptase to minus sense DNA. Here, the polymerase is
acting as an RNA-dependent DNA polymerase. Since reverse transcriptase is a DNA polymerase, it needs
a primer. This is a tRNA that is incorporated into the virus particle from the previous host cell.

4) RNA is displaced and degraded by a virus-encoded RNase H activity. Reverse transcriptase now acts
as a DNA-dependent DNA polymerase and copies the new DNA into a double strand DNA. This DNA form
of the virus is known as a the provirus.

5) Double strand DNA is circularized and integrated into host cell DNA (see below) using a virally encoded
integrase enzyme. This DNA is copied every time cellular DNA is copied. Thus, at this stage the provirus is
just like a normal cellular gene.
6) Full length, genomic RNA (plus sense) is copied from the integrated DNA by host RNA polymerase II
which normally copies a gene to mRNA. The genomic RNA is capped and poly adenylated, just as an
mRNA would be.

Since the full length genomic RNA is the same sense as message, it also acts as the mRNA for GAG and
POL polyproteins.

The genomic RNA is spliced by host nuclear enzymes to give mRNA for other proteins such as ENV. The
RNA of some more complex retroviruses such as HTLV-1 and HIV undergoes multiple splicing
(see chapter 7, HIV).

Note that mRNA comes from splicing genomic RNA or is the genomic RNA. As a result, both mRNA and
genomic RNA must be the same sense - since mRNA must be plus sense, the genomic RNA of all
retroviruses must also be plus sense.

An advantage of this mode of replication is that it allows growth in terminally differentiated cells since the
only host cell polymerase usurped by the virus is RNA polymerase II which is present in all cells.

MECHANISM OF VIRAL GENOME REPLICATION

If host RNA polymerase II is used to copy the DNA back to RNA, there are major problems with having a
DNA provirus form but an RNA genome in the mature virus particle

These problems include:

1) RNA polymerase II does not copy the upstream and down stream control sequences of genes. It only
copies the information necessary to make a protein

2) The lack of proof reading by RNA polymerase II

Failure of RNA polymerase II to copy the entire gene

The problem is that, when transcribing genes, RNA polymerase II needs control and recognition sites
upstream from the transcription initiation site. The upstream site at which the polymerase molecule binds is
called the PROMOTOR. Promotors are not themselves copied into mRNA since they have no function in
the translation of protein. After binding to the promotor, the polymerase begins transcription at a
downstream site, the RNA initiation site. The polymerase continues to transcribe DNA into RNA until it
reaches a termination/polyadenylation signal, part of which is not copied since,agaun, it also has no
function in the making of the protein. Furthermore, both up and downstream from the transcribed region
are control sequences that modulate the transcription of the gene. These are called ENHANCERS. These
are essential parts of any gene and must be present for RNA polymerase II to work but they are not copied
to RNA. This is because RNA polymerase II in the host cell has the function of making messenger RNA
which is dispensed with after translation. To make a protein, the actual mRNA molecule does not need the
control sequences of the original gene. Thus, the use of host RNA polymerase II means that the control
sequences in the original genome should not get into the RNA genome of progeny virions.

This means that either the DNA copy of the viral RNA genome virus must integrate into host DNA
downstream from a host promotor and upstream from host termination sites (a tall order indeed!) or it must
find a way of providing its own control sequences (which, as we said, are not copied into progeny
genome). It does the latter in a most complex manner.
What is the normal function of oncogenes?

As mentioned above, c-oncs are normal cellular genes that are expressed and function at some stage of
the life of the cell. We should expect them to be involved in DNA synthesis or perhaps the signaling
pathways that lead to proliferation. More than 40 oncogenes have been identified and there are probably a
few undiscovered ones.

We can sub-divide the cellular oncogenes into those that encode nuclear proteins and those that encode
extra-nuclear proteins. The latter are mostly associated with the plasma membrane of the cell (Figure 22
and 23).

Products of oncogenes that are nuclear proteins: e.g. myc, myb. These are involved in control of gene
expression (that is the regulation of transcription - they are transcription factors) or the control of DNA
replication. Neoplasia is associated with elevated transcription of the oncogene but strong expression is
not always necessary, rather there is a need to make the gene constitutively active rather than under
control of normal regulatory processes.

Products of oncogenes that are cytoplasmic or membrane-associated proteins: e.g. abl, src, ras.This
type does not exhibit altered expression but seems to convert from proto-oncogene to oncogene by
mutation. Thus, in src-induced tumors, strong over expression of the oncogene has no effect.

FUNCTION OF PROTO-ONCOGENE- ENCODED

EXAMPLE
PROTEINS
Control of DNA transcription (found in nucleus) myc
Signaling of hormone/growth factor binding such as
src is a membrane-bound tyr kinase.
a tyrosine kinase
GTP-binding proteins involved in signal
ras
transduction from a surface receptor to the nucleus
sis is an altered form of platelet-derived growth
Growth factors
factor B chain
erb-B is a homolog of the epidermal growth factor
receptor (it is also a tyrosine kinase). fms is a
Growth factor receptors
homolog of the macrophage colony-stimulating
factor (M-CSF) receptor

ANTI-ONCOGENES (TUMOR SUPPRESSOR GENES)

The way in which retroviruses cause tumor formation via oncogenes was established before anything was
known about how DNA tumor viruses cause tumors. Certainly, DNA tumor viruses carry oncogenes (e.g.
SV40 T-antigen) but how do these proteins, encoded in true viral genes with no cellular homologs, cause
the formation of tumors?

It has long been known that most tumors are the result of dominant mutations, i.e. a function is gained that
makes the cell grow when it should not (Figure 24). For example, as noted above, if we have a receptor
that sends a signal when it binds a growth factor by switching on its tyrosine kinase activity and that
receptor becomes mutated so that its tyrosine kinase activity is permanently activated, the cell will get the
aberrant growth signal even in the heterozygote. Thus the mutant allele is dominant over the normal allele.
p53 and human cancer

Over the past two decades, since its discovery in 1979, a gene known as the p53 gene (after the size of its
encoded protein) has been linked to many cancers including many that are inherited. In these inherited
cancers, it turns out that the p53 gene is mutated. Alterations in this protein seem to be the basis (direct or
indirect) of most human cancers. In total, 60% of human cancers involve p53. 80% of colon cancers
involve the p53 gene

Human cancers that involve p53

Cervix liver
Breast lung
Bladder skin
Prostate colon

Initially, it was thought that the p53 gene product caused cancers but further investigation showed the
opposite; p53 is, like the retinoblastoma gene product, a tumor suppressor. p53 protein has been referred
to as The Guardian of the Genome since it regulates multiple components of the DNA damage control
system.

How does p53 work in a functional cell? Normally, there are only a few of the suppressor p53 molecules in
a healthy cell and these are constantly turning over; but when the DNA becomes damaged (perhaps by
radiation or chemical mutagens) and DNA replication results, p53 turnover ceases. The rise in p53 stops
DNA replication.

p53 is a transcription factor. When it builds up, p53 binds to a specific site(s) on the chromosomes and
switches on other genes and these, in turn, shut down mitosis. p53 can also act in another way: When it
builds up it can set the cell on course to apoptosis. Whether or not p53 causes reversible growth arrest or
apoptosis depends on the state of cellular activation; for example, extensive, unrepaired DNA damage can
lead to sustained p53 production committing the cell to apoptosis. In inherited cancers, there is a mutation
in the p53 gene; often it is a single point mutation and the protein can no longer bind to its correct site on
the DNA and so cannot suppress DNA replication.

Like the Rb gene, product, you would expect the effects of p53 to be recessive since the second normal
p53 allele should make functional protein and should shut off DNA replication as usual; however, if you are
heterozygous for the mutation, you are, of course, only one mutation away from carcinogenesis. So why
do cells that are heterozygous for the p53 mutation also have problems? Unfortunately, p53 protein forms
tetramers in a ribbon-like array and so if half of the p53 proteins are mutant, there is a good chance that
each tetramer will have one mutant p53 molecule and this inactivates the tetramer, a dominant-negative
effect.

Although we have learned a lot from families that inherit p53 mutations, it is clear that most p53 mutations
come from non-inherited environmental factors: carcinogens (benzopyrene in smoke, aflatoxin in molds on
peanuts and corn, UV light) that result in point mutations. There are also gain of function p53 mutations
that lead to very aggressive tumors. These turn on DNA replication genes.

What has this got to do with DNA tumor viruses? Just as with retinoblastoma gene product, the presence
of a virus can mimic mutation and take the tumor suppressor out of action by complexing it in an inactive
form that cannot bind to the specific site on DNA. This is what appears to happen in hepatitis C which
causes hepatocellular carcinoma. In the case of a human papilloma virus-infected cell, p53 is bound by the
E6 protein and directed to a protease that recognizes a cleavage site in p53, thereby destroying it (Figure
26). In addition, E7 protein binds and inactivates Rb protein.

Much research is now going on to see whether one can introduce healthy p53 genes into cells to shut
down tumor growth.

Thus, our knowledge of how retroviruses cause cancer has led to an understanding of the formerly cryptic
manner in which DNA tumor viruses do the same thing.
Breast cancer

Breast cancer is cancer that forms in the cells of the breasts.

After skin cancer, breast cancer is the most common cancer diagnosed in women in the United
States. Breast cancer can occur in both men and women, but it's far more common in women.

Public support for breast cancer awareness and research funding has helped improve the
diagnosis and treatment of breast cancer. Breast cancer survival rates have increased, and the
number of deaths has been declining, thanks to a number of factors such as earlier detection, new
treatments and a better understanding of the disease.

Signs and symptoms of breast cancer may include:

 A breast lump or thickening that feels different from the surrounding tissue
 Bloody discharge from the nipple
 Change in the size or shape of a breast
 Changes to the skin over the breast, such as dimpling
 Inverted nipple
 Peeling, scaling or flaking of the nipple or breast skin
 Redness or pitting of the skin over your breast, like the skin of an orange
When to see a doctor
If you find a lump or other change in your breast — even if a recent mammogram was normal —
make an appointment with your doctor.

Causes
By Mayo Clinic Staff

It's not clear what causes breast cancer. Doctors know that breast cancer occurs when some
breast cells begin growing abnormally. These cells divide more rapidly than healthy cells do and
continue to accumulate, forming a lump or mass. The cells may spread (metastasize) through your
breast to your lymph nodes or to other parts of your body.

Breast cancer most often begins with cells in the milk-producing ducts (invasive ductal carcinoma).
Breast cancer may also begin in the glandular tissue called lobules (invasive lobular carcinoma) or
in other cells within the breast.

Researchers have identified things that can increase your risk of breast cancer. But it's not clear
why some people who have no risk factors develop cancer, yet other people with risk factors never
do. It's likely that breast cancer is caused by a complex interaction of your genetic makeup and
your environment.

Inherited breast cancer

Doctors estimate that only 5 to 10 percent of breast cancers are linked to gene mutations passed
through generations of a family. A number of inherited mutated genes that can increase the
likelihood of breast cancer have been identified. The most common are breast cancer gene 1
(BRCA1) and breast cancer gene 2 (BRCA2), both of which increase the risk of both breast and
ovarian cancer.

If you have a strong family history of breast cancer or other cancers, blood tests may help identify
mutations in BRCA or other genes that are being passed through your family.
Consider asking your doctor for a referral to a genetic counselor, who can review your family
health history. A genetic counselor can also discuss the benefits, risks and limitations of genetic
testing with you.

A BRCA mutation is a mutation in either of the genes BRCA1 and BRCA2. Harmful mutations
in these tumor suppressor genes produce a hereditary breast-ovarian cancer syndrome in affected
families. Mutations in BRCA1 and BRCA2 are uncommon, and breast cancer is relatively
common, so these mutations consequently account for only five to ten percent of all breast
cancer cases in women.[1]

Hundreds of different types of mutations in these genes have been identified. High-risk
mutations, which disable an important error-free DNA repair process (homology directed
repair), significantly increase the person's risk of developing breast cancer, ovarian cancer and
certain other cancers. Why BRCA1 and BRCA2 mutations lead preferentially to cancers of the
breast and ovary is not known, but lack ofBRCA1 function seems to lead to non-functional x-
chromosome inactivation. Not all mutations are high-risk; some appear to be harmless
variations. The cancer risk associated with any given mutation varies significantly and depends
on the exact type and location of the mutation and possibly other individual factors.

Women with harmful mutations in either BRCA1 or BRCA2 have risk of breast cancer that is
about five times the normal risk, and a risk of ovarian cancer that is about ten to thirty times
normal.[2] BRCA1mutations typically confer a higher risk of breast and ovarian cancer in women
than BRCA2 mutations. Having a high-risk mutation does not guarantee that the woman will
develop any type of cancer, or guarantee that any cancer that appears was actually caused by the
mutation, rather than some other factor, like alcohol consumption.

Mutations can be inherited from either parent and may be passed on to both sons and daughters.
Each child of a genetic carrier, regardless of sex, has a 50% chance of inheriting the mutated
gene from the parent who carries the mutation. As a result, half of the people with BRCA gene
mutations are male. The risk of BRCA-related breast cancers for men with the mutation is higher
than for other men, but still low.[3] However, BRCA mutations can increase the risk of other
cancers, such as colon cancer, pancreatic cancer, and prostate cancer.

Methods to diagnose the likelihood of a patient with mutations in BRCA1 and BRCA2 getting
cancer were covered by patents owned or controlled by Myriad Genetics.[4][5] Myriad's business
model of exclusively offering the diagnostic test led from Myriad being a startup in 1994 to
being a publicly traded company with 1200 employees and about $500M in annual revenue in
2012;[6] it also led to controversy over high prices and the inability to get second opinions from
other diagnostic labs, which in turn led to the landmark Association for Molecular Pathology v.
Myriad Genetics lawsuit

Risk factors
By Mayo Clinic Staff

A breast cancer risk factor is anything that makes it more likely you'll get breast cancer. But having
one or even several breast cancer risk factors doesn't necessarily mean you'll develop breast
cancer. Many women who develop breast cancer have no known risk factors other than simply
being women.

Factors that are associated with an increased risk of breast cancer include:

 Being female. Women are much more likely than men are to develop breast cancer.
 Increasing age. Your risk of breast cancer increases as you age.
 A personal history of breast cancer. If you've had breast cancer in one breast, you have an
increased risk of developing cancer in the other breast.
 A family history of breast cancer. If your mother, sister or daughter was diagnosed with breast
cancer, particularly at a young age, your risk of breast cancer is increased. Still, the majority of people
diagnosed with breast cancer have no family history of the disease.
 Inherited genes that increase cancer risk. Certain gene mutations that increase the risk of breast
cancer can be passed from parents to children. The most common gene mutations are referred to as
BRCA1 and BRCA2. These genes can greatly increase your risk of breast cancer and other cancers,
but they don't make cancer inevitable.
 Radiation exposure. If you received radiation treatments to your chest as a child or young adult, your
risk of breast cancer is increased.
 Obesity. Being obese increases your risk of breast cancer.
 Beginning your period at a younger age. Beginning your period before age 12 increases your risk of
breast cancer.
 Beginning menopause at an older age. If you began menopause at an older age, you're more likely
to develop breast cancer.
 Having your first child at an older age. Women who give birth to their first child after age 35 may
have an increased risk of breast cancer.
 Having never been pregnant. Women who have never been pregnant have a greater risk of breast
cancer than do women who have had one or more pregnancies.
 Postmenopausal hormone therapy. Women who take hormone therapy medications that combine
estrogen and progesterone to treat the signs and symptoms of menopause have an increased risk of
breast cancer. The risk of breast cancer decreases when women stop taking these medications.
 Drinking alcohol. Drinking alcohol increases the risk of breast cancer.
Tests and procedures used to diagnose breast cancer include:

 Breast exam. Your doctor will check both of your breasts, feeling for any lumps or other abnormalities.
 Mammogram. A mammogram is an X-ray of the breast. Mammograms are commonly used to screen
for breast cancer. If an abnormality is detected on a screening mammogram, your doctor may
recommend a diagnostic mammogram to further evaluate that abnormality.
 Breast ultrasound. Ultrasound uses sound waves to produce images of structures deep within the
body. Ultrasound may help distinguish between a solid mass and a fluid-filled cyst.
 Removing a sample of breast cells for testing (biopsy).Biopsy samples are sent to a laboratory for
analysis where experts determine whether the cells are cancerous. A biopsy sample is also analyzed to
determine the type of cells involved in the breast cancer, the aggressiveness (grade) of the cancer, and
whether the cancer cells have hormone receptors or other receptors that may influence your treatment
options.
 Breast magnetic resonance imaging (MRI). An MRI machine uses a magnet and radio waves to
create pictures of the interior of your breast. Before a breast MRI, you receive an injection of dye.
Other tests and procedures may be used depending on your situation.

Staging breast cancer

Once your doctor has diagnosed your breast cancer, he or she works to establish the extent
(stage) of your cancer. Your cancer's stage helps determine your prognosis and the best treatment
options. Complete information about your cancer's stage may not be available until after you
undergo breast cancer surgery.

Tests and procedures used to stage breast cancer may include:

 Blood tests, such as a complete blood count

 Mammogram of the other breast to look for signs of cancer
 Breast MRI
 Bone scan
 Computerized tomography (CT) scan
 Positron emission tomography (PET) scan
Not all women will need all of these tests and procedures. Your doctor selects the appropriate
tests based on your specific circumstances.

Breast cancer stages range from 0 to IV, with 0 indicating cancer that is very small and
noninvasive. Stage IV breast cancer, also called metastatic breast cancer, indicates cancer that
has spread to other areas of the body.

Breast cancer stages

The stage of breast cancer is one of the most important factors in evaluating treatment options. Our cancer
doctors use a variety of diagnostic tests to evaluate breast cancer and develop the appropriate treatment plan
for you.

Stage 0 (noninvasive, carcinoma in situ) breast cancer

In stage 0, there is no evidence of cancer cells breaking out of the part of the breast in which they started, or of
getting through to or invading neighboring normal tissue.

Stage I breast cancer

In stage I, the tumor measures up to two centimeters and no lymph nodes are involved.

Stage II (invasive) breast cancer

In stage II, the tumor measures between two to five centimeters, or the cancer has spread to the lymph nodes
under the arm on the same side as the breast cancer.

Stage III (locally advanced) breast cancer

In stage III, the tumor in the breast is more than two inches in diameter across and the cancer is extensive in the
underarm lymph nodes, or has spread to other lymph nodes or tissues near the breast.

Stage IV (metastatic) breast cancer

In stage IV, the cancer has spread beyond the breast, underarm and internal mammary lymph nodes to other
parts of the body near to or distant from the breast.

Recurrent breast cancer

In recurrent breast cancer, the disease has returned in spite of the initial treatment.
Pathophysiology[edit]
Main article: Carcinogenesis

Overview of signal transduction pathways involved in apoptosis. Mutations leading to loss of

apoptosis can lead to tumorigenesis.

Breast cancer, like other cancers, occurs because of an interaction between an environmental
(external) factor and a genetically susceptible host. Normal cells divide as many times as needed
and stop. They attach to other cells and stay in place in tissues. Cells become cancerous when
they lose their ability to stop dividing, to attach to other cells, to stay where they belong, and to
die at the proper time.

Normal cells will commit cell suicide (apoptosis) when they are no longer needed. Until then,
they are protected from cell suicide by several protein clusters and pathways. One of the
protective pathways is the PI3K/AKT pathway; another is the RAS/MEK/ERK pathway.
Sometimes the genes along these protective pathways are mutated in a way that turns them
permanently "on", rendering the cell incapable of committing suicide when it is no longer
needed. This is one of the steps that causes cancer in combination with other mutations.
Normally, the PTEN protein turns off the PI3K/AKT pathway when the cell is ready for cell
suicide. In some breast cancers, the gene for the PTEN protein is mutated, so the PI3K/AKT
pathway is stuck in the "on" position, and the cancer cell does not commit suicide.[61]

Mutations that can lead to breast cancer have been experimentally linked to estrogen
exposure.[62]

Failure of immune surveillance, the removal of malignant cells throughout one's life by the immune
system.[63] Abnormal growth factor signaling in the interaction between stromal cells and epithelial
cellscan facilitate malignant cell growth.[64][65] In breast adipose tissue, overexpression of leptin
leads to increased cell proliferation and cancer.[66]

In the United States, 10 to 20 percent of patients with breast cancer and patients with ovarian
cancer have a first- or second-degree relative with one of these diseases. The familial tendency
to develop these cancers is called hereditary breast–ovarian cancer syndrome. The best known of
these, the BRCA mutations, confer a lifetime risk of breast cancer of between 60 and 85 percent
and a lifetime risk of ovarian cancer of between 15 and 40 percent. Some mutations associated
with cancer, such as p53, BRCA1 and BRCA2, occur in mechanisms to correct errors in DNA.
These mutations are either inherited or acquired after birth. Presumably, they allow further
mutations, which allow uncontrolled division, lack of attachment, and metastasis to distant
organs.[46][67] However there is strong evidence of residual risk variation that goes well beyond
hereditary BRCA gene mutations between carrier families. This is caused by unobserved risk
factors.[68] This implicates environmental and other causes as triggers for breast cancers. The
inherited mutation in BRCA1 or BRCA2 genes can interfere with repair of DNA cross links and
DNA double strand breaks (known functions of the encoded protein).[69] These carcinogens
cause DNA damage such as DNA cross links and double strand breaks that often require repairs
by pathways containing BRCA1 and BRCA2.[70][71] However, mutations in BRCA genes account
for only 2 to 3 percent of all breast cancers.[72] Levin et al. say that cancer may not be inevitable
for all carriers of BRCA1 and BRCA2 mutations.[73] About half of hereditary breast–ovarian
cancer syndromes involve unknown genes.

GATA-3 directly controls the expression of estrogen receptor (ER) and other genes associated
with epithelial differentiation, and the loss of GATA-3 leads to loss of differentiation and poor
prognosis due to cancer cell invasion and metastasis.

EPIDEMIOLOGY OF BREAST CANCER

Worldwide, breast cancer is the most common invasive cancer in women. (The most common form of cancer is
non-invasive non-melanoma skin cancer; non-invasive cancers are generally easily cured, cause very few
deaths, and are routinely excluded from cancer statistics.) Breast cancer comprises 22.9% of invasive cancers in
women[2] and 16% of all female cancers.[3]

In 2008, breast cancer caused 458,503 deaths worldwide (13.7% of cancer deaths in women and 6.0% of all
cancer deaths for men and women together).[2] Lung cancer, the second most common cause of cancer-related
death in women, caused 12.8% of cancer deaths in women (18.2% of all cancer deaths for men and women
together).[2]

The number of cases worldwide has significantly increased since the 1970s, a phenomenon partly attributed to
the modern lifestyles.[4][5]

By region[edit]
The incidence of breast cancer varies greatly around the world: it is lowest in less-developed countries and
greatest in the more-developed countries. In the twelve world regions, the annual age-standardized incidence
rates per 100,000 women are as follows: in Eastern Asia, 18; South Central Asia, 22; sub-Saharan Africa, 22;
South-Eastern Asia, 26; North Africa and Western Asia, 28; South and Central America, 42; Eastern Europe, 49;
Southern Europe, 56; Northern Europe, 73; Oceania, 74; Western Europe, 78; and in North America, 90.[7]

United States[edit]

Cancer occurrence in females in the US[8]

Cancer occurrence in Women in the US by mortality.[8]

The lifetime risk for breast cancer in the United States is usually given as about 1 in 8 (12%) of women by age
95, with a 1 in 35 (3%) chance of dying from breast cancer.[9] This calculation assumes that all women live to at
least age 95, except for those who die from breast cancer before age 95.[10] Recent work, using real-world
numbers, indicate that the actual risk is probably less than half the theoretical risk.[11]

The United States has the highest annual incidence rates of breast cancer in the world; 128.6 per 100,000 in
whites and 112.6 per 100,000 among African Americans.[9][12] It is the second-most common cancer (after skin
cancer) and the second-most common cause of cancer death (after lung cancer) in women.[9] In 2007, breast
cancer was expected to cause 40,910 deaths in the US (7% of cancer deaths; almost 2% of all deaths).[13] This
figure includes 450-500 annual deaths among men out of 2000 cancer cases.[14]

In the US, both incidence and death rates for breast cancer have been declining in the last few years in Native
Americans and Alaskan Natives.[13][15] Nevertheless, a US study conducted in 2005 indicated that breast cancer
remains the most feared disease,[16] even though heart disease is a much more common cause of death among
women.[17] Studies suggest that women overestimate their risk of breast cancer.[18]
UK[edit]

Breast cancer incidence by age in women (UK) 2006-08[19]

Breast cancer is the most common cancer in the UK (around 49,900 women and 350 men were diagnosed with
the disease in 2011), and it is the third most common cause of cancer death (around 11,600 women and 75 men
died in 2012).[20]

Developing countries[edit]
"Breast cancer in less developed countries, such as those in South America, is a major public health issue. It is a
leading cause of cancer-related deaths in women in countries such as Argentina, Uruguay, and Brazil. The
expected numbers of new cases and deaths due to breast cancer in South America for the year 2001 are
approximately 70,000 and 30,000, respectively."[21] However, because of a lack of funding and resources,
treatment is not always available to those suffering with breast cancer