The following image depicts the abnormal cells
of a breast cancer.
Breast cancer is a major health concern. An estimated 216,000 new cases
of invasive breast cancer are reported each year in the U.S. resulting
in more than 40,000 deaths. More than a million women throughout the world
were diagnosed with breast cancer in the year 2000. Sixty years ago, a
woman's likelihood of developing breast cancer was 1 in 22; it is now
1 in 8. Breast cancer rates are highest in developed, industrialized regions
such as the United States and women in industrialized nations with a Western
lifestyle experience breast cancer at rates five times higher than those
of developing countries.
What causes breast cancer? Like most of the serious
health issues which face us today (such as cardiovascular disease, asthma,
and weight gain), breast cancer is a multifactorial disorder. This means
that breast cancer risk is determined by a variety of genes and environmental
factors. While one woman's breast cancer may be primarily inherited, another
woman's breast cancer may be primarily caused by environmental factors.
Rather than a case of nature vs. nurture, it is more appropriate to ask
how a woman's environment is interacting with her genetic makeup.
Although a diversity of factors affect breast cancer risk, the lifelong
exposure to estrogen seems to be the primary risk factor of breast cancer.
In women, estrogens promote the growth and differentiation of female reproductive
structures, maintain bone mass, serve to lessen cardiovascular disease,
and influence mood, cognition, and hormone release. Estrogen is synthesized
from androgens in both men and women by the gonads, brain, adipose, and
the liver by the aromatase cytochrome P450 19 enzyme. Because the cytochrome
P450 enzymes control the synthesis and conversion of estrogens, variations
(polymorphisms) in these genes and their expression levels are relevant
to determining breast cancer risk. Polymorphisms in several genes which
synthesize or metabolize estrogen (CYP1A1, CYP17, CYP19, CYP1B1, and COMT)
have been associated with breast cancer.
Since estrogen exposure is a primary risk factor in breast cancer, the
number of menstrual cycles that a woman will undergo in her lifetime is
a factor in determining this risk. The lifetime number of menstrual cycles
in increased by an earlier the age of menarche and a later age of menopause.
After menopause, the reduction of ovarian hormones such as estrogen can
cause a variety of undesirable effects in older women such as bone loss
and osteoporosis. Although hormone replacement therapy (HRT) can alleviate
many of these problems, HRT increases the risk of breast cancer.
Estrogen receptors are promiscuous and can bind to a variety of compounds.
As a result, a number of structurally unrelated molecules originating
in sources as varied as plants and plastics can produce molecules which
simulate the effects of estrogen in breast tissue. Phytoestrogens are
plant compounds which can either mimic the effects of estrogen in binding
estrogen receptors or alter the concentration of estrogen receptors. Environmental
estrogens are thought to be factors which are increasing the rates of
breast cancer, decreasing average sperm counts in men. Bisphenol-A (BPA)
is a synthetic component used in the manufacture of the plastics which
compose food and drink containers (including baby bottles) and medical
equipment. BPA can bind estrogen receptors and mimics some of the effects
of estrogen. Exposure to DDT in girls has been associated with elevated
levels of breast cancer later in life.
The majority of breast cancers occur in the upper outer quadrant of the
breast (31% measured according to early studies; as many as 60% in modern
studies), suggesting that cosmetics or deodorant may be implicated in
causing breast cancer. Some cosmetic components have been isolated from
breast tissue while others have been isolated from breast milk. A number
of cosmetic components display estrogen-like activity and aluminum salts
from antiperspirants affect estrogen activity.
Obesity is a more serious risk factor for the development of breast cancer
than other risk factors such as hormone replacement therapy, early menarche,
late menopause, late birth of first child, and alcohol intake. Adipose
cells can synthesize their own estrogen. Alcohol consumption is associated
with increased blood estrogen levels in males and females. As a result,
alcohol consumption increases breast cancer risk.
FACTORS OTHER THAN ESTROGEN
A number of other signaling molecules in the body can increase the risk
of breast cancer including prolactin, neuregulin, insulin, insulin-like
growth factor, and genes of the EGFR/HER gene family. Diabetes increases
the risk of a number of cancers, such as breast, endometrial, colon, and
pancreatic cancers. While progesterone and androgens usually inhibit cell
division in normal breast cells, cancer cells are by definition abnormal.
Some cancers have been promoted by progesterone and androgens. Some breast
cancer cells express leptin receptors and leptin stimulates their growth.
Once a normal cell has been instructed to divide, a cascade of factors
will be activated in order to initiate cell division. In some cases, mutations
cause these factors to promote cell division inappropriately. A variety
of kinase enzymes (which activate proteins by adding a phosphate to specific
spots of the protein) can be implicated in abnormal growth in breast cells
including MAP kinases, Src, and checkpoint kianses.
PROTEINS ACTIVE IN THE NUCLEUS
At some point, cellular signaling pathways can activate new gene transcription
through transcription factors. Activated estrogen, progesterone, and androgen
receptors are transcription factors, as are a number of other proteins
which function in breast cell division. Cyclins are proteins which promote
the progression of cells through various stages of the cell cycle (such
as cyclin D1which mediates the increased cellular proliferation which
results from estrogen receptor activity).
Although there are a number of genes which may contribute to inherited
risk, the primary genes identified so far are BRCA1, BRCA2, and p53. BRCA1
was first discovered in 1994. Mutant BRCA1 alleles are associated with
increased risk of breast, cervical, uterine, prostate, and pancreatic
cancers. BRCA polymorphisms which affect cancer risk can vary in frequency
throughout different human populations. BRCA1 regulates the transcription
of genes, inhibits estrogen receptors, promotes the activity of androgen
receptors, and increases the production of anti-oxidants and a number
of genes which inhibit cell growth.
The tumor suppressor protein p53 is mutated in about half of human cancers.
Upon activation, p53 travels to the nucleus where it functions as a transcription
factor promoting the expression of genes which stop the cell cycle and/or
promote apoptosis (programmed cell death). Other mutations in proteins
which function in DNA repair are linked to breast cancer, such as MSH2,
ATM, and MLH1.
STILL MORE FACTORS
Chromosomal abnormalities are associated with a number of cancers, including
breast cancer. Specifically, changes to the structure of chromosomes 1,
3, 6, 11, 13, 16, and 17 have been linked to breast cancer, as have changes
in the number of chromosomes 7, 8, 12, and 20. Amplification in the copy
number and increased expression of a number of genes can promote breast
cancer such as MYC, HER2, BCL2, VEGF, and others.
Chronic inflammation is a factor in a number of cancers. Chronic inflammation
produces reactive oxygen species (ROS), whose levels are increased in
many malignant breast cells. Breast cancer tissue can possess papillomavirus
sequences, indicating that HPV may be a risk factor in breast cancer.
Increased breast density is a risk factor for breast cancer. Alcohol intake,
polymorphisms of several genes, nulliparity, and advanced or very young
age at first childbirth are factors which increase breast density.
Those who undergo radiological studies of their thymus or lungs (as in
tuberculosis) experience increased risk of breast cancer due to radiation
A diet rich in fruits and vegetables reduces the risk of cancer and a
number of vitamins (beta carotene, retinoic acid, vitamin C, vitamin D,
and vitamin E) seem to offer some degree of protection from breast cancer
development. Lignans, components of flax seed, may reduce breast cancer
risk by inhibiting aromatase and thus the production of estrogen.
It appears that the breast has not completed its
development prior to the completion of the first full-term pregnancy.
The later in life that this first pregnancy occurs (or the possibility
that it never occurs), the more susceptible the breast is to develop cancer.
If the first pregnancy occurs after an age of 35 or so, it appears this
is also a risk factor for breast cancer, perhaps because of the effects
of the pregnancy growth factors on breast tissue which has differentiated
along an alternate path.
Like most of the common health disorders in our modern world, breast cancer
risk is a multifactorial trait which is determined by multiple genes,
multiple environmental factors, and the interaction of a person's environment
with their genetic makeup. If you would like to read a more technical
description of breast cancer, you can find more information at http://bio.sunyorange.edu
or simply click on the following link: