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Cancer is a disease characterized by a loss in the normal control mechanisms that govern cell survival, proliferation, and differentiation. Cancer is caused by changes in a cell's DNA - its genetic "blueprint" (American Cancer Society, 2012).Some of these changes may be inherited from our parents, while others may be caused by outside exposures, which are often referred to as environmental factors (National Cancer Institute, 2012).. Environmental factors can include a wide range of exposures, such as lifestyle factors that are nutrition, tobacco use and physical activity, naturally occurring exposures like ultraviolet light, radon gas, and infectious agent, workplace exposure, household exposure, pollution and last but not least medical treatment which include chemotherapy, radiation, immune system-suppressing drugs (American Cancer Society, 2012). These causal factors may act together or in sequence to initiate or promote carcinogenesis. The development of most cancers requires multiple steps that occur over many years. Certain types of cancer can be prevented by eliminating exposure to tobacco and other factors that initiate or accelerate this process. Other potential malignancies can be detected before cells become cancerous or at an early stage, when the disease is most treatable (National Cancer Institute, 2012).
A report from American Cancer Society (2012), approximately 1,690,000 new cancer cases will be diagnosed and 577,000 Americans will ultimately die of cancer. National Cancer Registry (2007) stated a total of 18,219 new cancer cases were diagnosed in that year and registered. It comprises of 8,123 (44.6%) males and 10,096 (55.4%) females.
Breast cancer was the most common cancer in females and also the first most common cancer among population regardless of sex in Malaysia. According to NCR (2007), there were 3,242 female breast cancer cases diagnosed in 2007 which accounted for 18.1% of all cancer cases reported and 32.1% of all are female's. The incidence of breast cancer was highest among Chinese where the age-standardised rate (ASR) was 38.1 per 100,000 population followed by Indian and Malay with the ASR of 33.7 per 100,000 population and 25.4 per 100,000 populations respectively. The percentage of breast cancer detected at stage I and II was 58% (NCR ,2007).
Estrogen is a natural steroid hormone found in our body. Estrogen comprises estradiol, estrone and estriol. The most active estrogen which is estradiol is produced by ovaries. Estradiol also, plays an important role in the progression of breast cancer, and a majority of the human breast cancers start out as estrogen dependent and express the estrogen receptor (ER). The biological effects of estrogen are mediated by its binding to one of the structurally and functionally distinct ERs which are ERÎ± and ERÎ² (Saha Roy and K. Vadlamudi, 2012).
The main good effects of estrogen include its roles in programming the breast and uterus for sexual reproduction, controlling cholesterol production in ways that limit the buildup of plaque in the coronary arteries, and preserving bone strength by helping to maintain the proper balance between bone buildup and breakdown (National Cancer Institute, 2012).
Despite all these important beneficial effects, estrogen can also be harmful. Estrogen is able to promote the proliferation of cells in the breast and uterus in which way it is the most serious problem. Although estrogen does not appear to directly cause the DNA mutations that trigger the development of human cancer, its ability to stimulate cell proliferation in its normal roles, can also increase a woman's chance of developing breast or uterine cancer (National Cancer Institute, 2012). There are three mechanisms that have been considered to be responsible for the carcinogenicity of estrogens. They are 1) receptor-mediated hormonal activity, 2) a cytochrome P450 (CYP)-mediated metabolic activation, which elicits direct genotoxic effects by increasing mutation rates, and 3) the induction of aneuploidy by estrogen (Russo et al., 2003).
An estrogen receptor is a protein molecule found inside the cells that are targets for estrogen action. Estrogen receptors contain a specific site to which only estrogens (or closely related molecules) can bind.
When estrogen molecules circulate in the bloodstream and move throughout the body, only cells that contain estrogen receptors are affected. Estrogen receptors normally reside in the cell's nucleus, along with DNA molecules.
When the estrogen molecules are absence, these estrogen receptors are inactive and have no influence on DNA . But once an estrogen molecule enters a cell and passes into the nucleus, the estrogen binds to its receptor, thereby causing a conformational change to the receptor. Later, this estrogen-receptor complex then binds to specific DNA sites, called estrogen response elements, which are located near genes that are controlled by estrogen.
After it has become attached to estrogen response elements in DNA, this estrogen-receptor complex binds to coactivator proteins and more nearby genes become active. The active genes produce molecules of messenger RNA, which guide the synthesis of specific proteins. These proteins can then influence cell behavior in different ways, depending on the cell type involved.
ERÎ± is the major subtype in the mammary epithelium and plays an important role in mammary gland biology as well as breast cancer development. ERÎ± is a ligand-dependent transcription factor that modulates gene transcription via recruitment to the target gene chromatin (Mann et al., 2011). Recent mechanistic studies have highlight a role of estrogen estrogen-induce rapid ERÎ± extranuclear signaling in facilitating the metastatic process (Saha Roy and K. Vadlamudi, 2012).
Emerging evidence suggests that ERÎ± signaling has the potential to contribute to epigenetic changes. Several histone modifications at the ERÎ± target gene promoters which are acetylation, phosphorylation and methylation via dynamic interactions with histone modifying enzymes are due to estrogen. Deregulation of enzymes involved in the ERÎ± - mediated epigenetic pathway could play a vital role in ERÎ± driven neoplastic processes. Unlike genetic alterations, epigenetic changes are reversible, and hence offer novel therapeutic opportunities to reverse ERÎ± driven epigenetic changes (Mann et al., 2011).
Estrogen receptor negative (ER -)
ER-negative breast cancers are often considered to be the result of tumor progression from ER-positive premalignant lesions or ER-positive breast cancers by genetic alteration such asgene instability, loss of heterozygosity, and exon deletion epigenetic alteration such as promoter methylation or ER protein degradation in proteasome after hypoxia in non-vascularized tumor (Rochefort et al., 2003).
How to treat cancer?
Paclitaxel and chemotherapy
Paclitaxel as promising anticancer drugs
Anticancer mechanisms of paclitaxel
Clinical dosage form
Intravenous (i.v) injection administration
Problems related to paclitaxel
Nanodelivery system formulation of paclitaxel
In vitro evaluation
Cytotoxicity study of drug-loaded polymeric nanoparticles