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This chapter will focus on previous studies which will clarify understanding about this topic. It contains researches about breast cancer, cytotoxic mechanisms toward breast cancer cells, pure compounds that have cytotoxic effects against breast cancer and data mining techniques that will be used in developing database for pure compounds that have cytotoxic effects on breast cancer.
Human breast is composed of two main types of tissues which are glandular tissues and stromal (supporting) tissues. Each tissue has different structure and function, glandular tissues is the one contain milk-producing lobules and milk passages (ducts) to nipple while stromal tissues include fatty and fibrous connective tissue that surrounding the ducts and lobules, blood vessel, and lymphatic vessels. (MEDtropolis, 2006; Imaginis.com) Slightly changes in any of both tissues may cause benign breast condition.
Breast cancer can be classified as two big branches which are noninvasive and invasive. Noninvasive breast cancer consists of ductal carcinoma in situ (DCIS; also called intraductal carcinoma) and lobular carcinoma in situ (LCIS). Ductal carcinoma in situ resemble of cancer cell in the lining of duct, it is non-invasive, early cancer, yet, if it left untreated, it may sometimes progress to an invasive, infiltrating ductal breast cancer. It is the most common type of noninvasive breast cancer. Technically, lobular carcinoma in situ (LCIS) is not a cancer but is a marker for an increased risk of invasive cancer the same or both breast. (The New York Times)
Invasive cancer occurs when cancer cells spread beyond the basement membrane, which covers the underlying connective tissue in the breast. The tissue is rich in blood vessel and lymphatic channels that are capable of carrying cancer cells beyond the breast. Invasive breast cancer includes invasive or infiltrating ductal carcinoma and invasive or infiltrating lobular carcinoma. Invasive ductal carcinoma is breast cancer that penetrates the wall of milk-passage duct and it occurs between 70 to 80% of all breast cancer cases. For invasive lobular carcinoma, it has spread through the wall of milk-producing lobule and accounts for 10 to 15% of all breast cancer cases. It sometimes appears in both breast, sometimes appears in several locations. (The New York Times)
The less common forms of breast cancer includes medullary carcinoma, mucinous carcinoma, tubular carcinoma, inflammatory breast cancer, Paget's disease of the nipple, and phylloides tumor. Medullary carcinoma is an invasive breast cancer that forms a distinct boundary between tumor tissue and normal tissue; mucinous carcinoma is formed by mucus-producing cancer cells. Tubular carcinoma is a special type of invasive breast carcinoma. For inflammatory breast cancer, its appearance of inflamed breast (red and warm) with dimples and/or thick ridges caused by cancer cells blocking lymph vessels or channels in the skin over the breast, and it is extremely fast-growing. Paget's disease of the nipple is a rare form of breast cancer that begins in the milk ducts and spreads to the skin of the nipple and areola, Paget's disease of the nipple. Lastly, phylloides tumors can be either benign or malignant; it develops in the connective tissues of the breast and may be treated by surgical removal. (Imaginis.com)
Factors such as age, race and ethnicity, family and personal history, physical characteristics, environmental factors, genetic factors, exposure to estrogen, and other factors may also be the reasons that cause breast cancer.
Here, I will focus more on genetic factors and exposure to estrogen and some environmental factors.
There are 5 to 10% of breast cancer cases are due to inherited mutations in genes known as BRCA1 or BRCA2 are responsible for most cases of hereditary breast cancers, ovarian cancers, or both in families with a history of these cancers. BRCA gene mutations are present in only about 0.5% of the overall population. However, certain ethnic groups - such as Jewish women of Eastern European (Ashkenazi) decent - have a higher prevalence (2.5%) of BRCA gene mutations. BRCA gene mutations are also seen in some African-American and Hispanic women. In general, a woman is considered at high risk for BRCA genes if she has a first-degree relative (mother, daughter, or sister) or several second-degree relatives (grandmother, aunt) diagnosed with breast or ovarian cancer. Women who do not have a family history of breast cancer have a low probability of inheriting BRCA genes and do not need to be tested.
The relevance of the inherited BRCA1 or BRCA2 mutations to survival is controversial. Some studies have suggested that these mutations are linked to less lethal breast cancer. Others suggest that they do not change prognosis or may worsen it. Women with these genetic mutations do have a greater risk for a new cancer to develop. Patients with BRCA1 mutations tend to develop tumors that are hormone receptor negative, which can behave more aggressively. Other genes associated with increased hereditary breast cancer risk include p53, CHEK2, ATM, and PTEN.
Growth of breast tissue is highly sensitive to estrogens, therefore, the more estrogen a woman is exposed to over her lifetime, the higher her risk for breast cancer. Early age at menarche (first menstrual period) or later age at menopause may slightly increase a woman's risk for breast cancer, this is due to exposure of estrogen is longer. Besides that, women who have never had children or who had their first child after age 30 may have a slightly increased breast cancer risk. Having children at an early age, and having multiple pregnancies, reduces breast cancer risk. Scientific evidence shows there is no association between abortion and increased breast cancer risk. On the other hand, studies have been mixed on whether breast-feeding decreases breast cancer risk. Breast-feeding reduces a woman's total number of menstrual cycles and thereby estrogen exposure, which may account for its possible protective effects. Some studies suggest that the longer a woman breast-feeds, the lower her risk and that breast-feeding may be most protective for women with a family history of breast cancer. Although studies have been conflicting about whether estrogen in oral contraceptives increases the chances for breast cancer, the most recent research indicates that current or former oral contraceptive use does not significantly increase breast cancer risk. Women who have used oral contraceptives may have slightly more risk for breast cancer than women who have never used them, but this risk declines once a woman stops using birth control pills.
Many studies have reported a higher risk for breast cancer in postmenopausal women who take combination hormone replacement therapy (HRT), which contains both estrogen and progesterone. Combination HRT is used by women who have a uterus, because estrogen alone can increase the risk of uterine cancer. Estrogen-only hormone replacement therapy is prescribed for women who have had a hysterectomy. According to the most recent studies, long-term use (about 5 years or more) of combination HRT increases the risk of developing and dying from breast cancer. This risk then decreases within 5 years of stopping combination HRT. The North American Menopause Society recommends that women who are at risk for breast cancer should avoid hormone therapy and try other options to manage menopausal symptoms such as hot flashes. Most doctors recommend that women use HRT only for short-term relief of menopausal symptoms. In recent years, rates of breast cancer have decreased as fewer women have opted for HRT. Women who take HRT should be aware that they need regular mammogram screenings, because HRT increases breast cancer density, making mammograms more difficult to read.
There are certain breast conditions may increase the risk for breast cancers which are dense breast tissue are associated with a higher risk for breast cancer. Studies suggest that women with highly dense tissue have 2 - 6 times the risk of women with the least dense tissue. Genetic factors play a large role in breast density. Hormone replacement therapy also increases breast density. In addition, dense breasts make mammograms more difficult to read, which increases the likelihood of missing early signs of cancer.
Estrogen is involved in building bone mass. Therefore, women with heavy, dense bones are likely to have higher estrogen levels and to be at greater risk for breast cancer. Some studies have found a greater risk for breast cancer in taller women, possibly due to the higher estrogen levels associated with greater bone growth.
Chemicals with estrogen-like effects, called xenoestrogens, have been under suspicion for years. There has been particular concern with pesticides containing organochlorines (DDT and its metabolites, such as dieldrin) and pyrethroids (permethrin), but at this time evidence of any causal association is very weak.
Women who took diethylstilbestrol (DES) to prevent miscarriage have a slightly increased risk for breast cancer. There may also be a slightly increased risk for their daughters (commonly called "DES daughters"), who were exposed to the drug when their mothers took it during pregnancy.
Heavy exposure to radiation is a significant risk factor for breast cancer. Girls who receive high-dose radiation therapy for cancer face an increased risk for breast cancer in adulthood. Low-dose radiation exposure before age 20 may increase the risk for women with BRCA genetic mutations. (The New York Times)
Breast cancer cells may contain receptors, or binding sites, for the hormones estrogen and progesterone. Cells containing these binding sites are known as hormone receptor-positive cells. If cells lack these connectors, they are called hormone receptor-negative cells. About 75% of breast cancers are estrogen receptor-positive (ER-positive, or ER+). About 65% of ER-positive breast cancers are also progesterone receptor-positive (PR-positive, or PR+). Cells that have receptors for one of these hormones, or both of them, are considered hormone receptor-positive.
Hormone receptor-positive cancer is also called "hormone sensitive" because it responds to hormone therapy such as tamoxifen or aromatase inhibitors. Hormone receptor-negative tumors are referred to as "hormone insensitive" or "hormone resistant."
Women have a better prognosis if their tumors are hormone receptor-positive because these cells grow more slowly than receptor-negative cells. In addition, women with hormone receptor-positive cancer have more treatment options. (Hormone receptor-negative tumors can be treated only with chemotherapy.) Recent declines in breast cancer mortality rates have been most significant among women with estrogen receptor-positive tumors, due in part to the widespread use of post-surgical hormone drug therapy.
Tumor markers are proteins found in blood or urine when cancer is present. Although they are not used to diagnose cancer, the presence of certain markers can help predict how aggressive a patient's cancer may be and how well the cancer may respond to certain types of drugs. Tumor markers relevant for breast cancer prognosis include: HER2. The American Cancer Society recommends that all women newly diagnosed with breast cancer get a biopsy test for a growth-promoting protein called HER2/neu. HER2-positive cancer usually occurs in younger women and is more quickly-growing and aggressive than other types of breast cancer. The HER2 marker is present in about 20% of cases of invasive breast cancer. Two types of tests are used to detect HER2: Immunohistochemistry (IHC) and Fluorescence in-situ hybridization (FISH). Either test may be used as long as it is performed by an accredited laboratory. Tests that are not clearly positive or negative should be repeated. Other markers that may be evaluated include CA 15-3, CA 27.29, CEA, ER, PgR, uPA, and PAI-1.
Gene expression profiling tests (Oncotype DX, MammaPrint) examine a set of genes in tumor tissue to determine the likelihood of breast cancer recurrence. These tests are also used to help determine whether adjuvant (following surgery) drug treatments should be given. The American Society of Clinical Oncology and the National Comprehensive Cancer Network now recommend that gene expression profiling tests be administered to newly diagnosed patients with node-negative, estrogen-receptor-positive breast cancer. Based on the results, a doctor can decide whether a patient who has had surgery may benefit from chemotherapy. (The New York Times)
2.3 Cytotoxic Mechanisms towards Breast Cancer Cells
2.4 Several Pure Compounds that have Cytotoxic Effects against Breast Cancer Cells
Despite some concerns that infertility treatments using the drug clomiphene may increase the risk for breast cancer, most studies do not show an association. Some studies indicate that ovulation induction with clomiphene may actually decrease breast cancer risk. (Clomphine is related to tamoxifen, a drug that is used for breast cancer prevention in high-risk women.)
Treatment with trastuzumab (Herceptin) or lapatinib (Tykerb) may help women who test positive for HER2. In 2008, the FDA approved a new genetic test (Spot-Light) that can help determine which patients with HER2-positive breast cancer may be good candidates for trastuzumab treatment.
Hormonal status refers to the estrogen receptor (ER) or progesterone receptor (PR) status of an invasive breast cancer. Patients whose tumors are found to be estrogen-receptor-positive (ER+) or progesterone-receptor-positive (PR+) can be treated by hormonal therapy to help prevent distant spread of the tumor. Treatment for ER+/PR+ patients in the adjuvant setting with invasive breast cancer includes estrogen-receptor blockade with medications like tamoxifen. Newer effective hormonal therapy includes arromatase inhibitors such as Arimidex ®, letrozole, or exemestane. They are used to prevent your body from making estrogen. They are given with or without chemotherapy. Hormonal therapy can also be given safely with radiation.
Additional tests may include S-Phase, Ki67, and HER2/neu. You measure the S-Phase or Ki67 to give an indication of how rapidly the cancerous cells are dividing. The HER 2 gene product can be tested for over expression, which is associated with tumors that are more aggressive. Seventy-five percent of breast cancer tumors are HER 2 negative. Metastatic breast cancer that is HER 2 positive can also be treated with Herceptin (trastuzumab). Herceptin is also being given along with chemotherapy and hormonal therapy in the adjuvant setting, as well as with metastatic disease. (MEDtropolis, 2006)