BREAST CANCER

The following image depicts the abnormal cells of a breast cancer.

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.

ESTROGEN
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 exposure.
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.

CONCLUSION
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:


BREAST CANCER