Definition
Cancer is a condition where cells have lost normal control mechanisms, so that experienced abnormal growth, rapid and uncontrolled.
In addition, breast cancer (mammary carcinoma) is defined as a disease of malignant neoplasms that originate from the parenchyma. The disease is by the Word Health Organization (WHO) included in the International Classification of Diseases (ICD) with the code number 17.
Some types of breast cancers often show hormone dysregulation HGF and Met oncogenes, and excess expression of enzymes TOD-6
Transformation
Cancer cells are formed from normal cells in a complex process called transformation, which consists of initiation and promotion stages.
Phase initiation
At the initiation stage occurs a change in the genetic material of cells that provoke cell becomes malignant. Changes in the genetic material of cells is caused by an agency called carcinogens, which can include chemicals, viruses, radiation (irradiation) or sunlight. But not all cells have the same sensitivity to a carcinogen. Genetic abnormalities in cells or other material called a promoter, causing the cells more susceptible to a carcinogen
Progesterone, a hormone that induces ductal side-branching in the mammary gland and breast epithelial cells lobualveologenesis on, estimated to act as an activator trajectory tumorigenesis in breast cells induced by carcinogens. Progestin to induce transcription of cell cycle regulator cyclin D1 to secreted epithelial cells. Secretion can be increased about 5 to 7-fold by the hormone estrogen stimulation, because estrogen is the hormone that activates the expression of progesterone on epithelial cells perceiving. In addition, progesterone also induces the secretion of calcitonin gland morphogenesis and luminal cells.
Promotion phase
At the stage of promotion, a cell that has undergone initiation to become malignant. Cells that have not passed the initiation stage will not be affected by the campaign. Because it takes several factors to the occurrence of malignancies (combination of a sensitive cell and a carcinogen).
Phase metastasis
Metastasis to the bone is a frequently occur in breast cancer, some of which are accompanied by other complications such as simtoma hypercalcaemia, pathological fractures or spinal cord compression. is thus osteolytic metastases, which means that osteoclast induction of cancer cells is a mediator osteolysis and influence differentiation and activity of osteoblasts and osteoclasts to increase bone resorption another.
Bone is made of a unique network of matrix proteins that contain crystals of calcium with hydroxyappatite so that the mechanism used by cancer cells to make room on the extracellular matrix with the use of matrix metalloproteinase enzymes are not effective. Therefore, allowing the bone resorption caused by neoplastic invasion of the interaction between breast cancer cells with endothelial cells mediated by VEGF expression. VEGF is an angiogenic mitogen that react positively with endothelial cells. Without the negative angiogenic factors such as angiostatin, endothelial cells that interact with cancer cells through the perceiving VEGF VEGFR-1 and VEGFR-2, will shed the extracellular matrix, migrate and form tubules.
Classification
MCF-7 cells, T-47D cells, cells MDA-MB-231 cells, MDA-MB-468 cells, BT-20 and BT-549 cells.
Histopathology
Based on the WHO histological classification of breast tumors, breast cancers are classified as follows:
1. Non-invasive carcinoma
* Non-invasive ductal carcinoma
* Lobular carcinoma in there
2. Invasive carcinoma
* Invasive ductal carcinoma
o Papilobular carcinoma
o Solid-tubular carcinoma
o Scirrhous carcinoma
o Special types
o Mucinous carcinoma
o Medulare carcinoma
* Invasive lobular carcinoma
o adenoid cystic carcinoma
o squamos cell carcinoma
o spindle cell carcinoma
o Apocrin carcinoma
o Carcinoma with metaplasia of cartilage or osseous metaplasia
o Tubular carcinoma
o secretory carcinoma
o Other
3. Paget's Disease
Stage
Staging of cancer is a condition of appraisal physicians when diagnosing an illness suffered by cancer patients, have what extent the level of either the spread of cancer to other organs or surrounding tissues or spread elsewhere. Stadium is only known to a malignant tumor or cancer and not in any benign tumors. To determine the stage, must be supported by clinical examination and other investigations of histopathology or PA, X-rays, ultrasound, and if possible with a CT scan, scintigrafi, etc.. There are so many ways to determine the stage, but the most widely adopted today is the stage of cancer based on TNM classification system recommended by the UICC (International Union Against Cancer of the World Health Organization) / AJCC (American Joint Committee On Cancer, sponsored by the American Cancer Society and American College of Surgeons).
TNM System
TNM is an abbreviation of "T" ie tumor size or tumor size, "N" ie nodes or regional lymph nodes and the "M" that is distant metastasis or spread. These three factors T, N, and M, both clinically assessed before surgery, even after surgery and histopathological examination (PA). In breast cancer, TNM assessment as follows:
* T (tumor size), tumor size:
o T 0: not found the primary tumor
o T 1: the size of the tumor diameter of 2 cm or less
o T 2: tumor size of 2-5 cm diameter
o Q 3: The size of the tumor diameter> 5 cm
o T 4: tumor size whatever, but there have been spread to the skin or chest wall or both, may include ulcers, edema, or swelling, redness of breast skin or a small lump on the skin outside the main tumor
* N (nodes), regional lymph nodes (lymph nodes):
o N 0: there are no metastases to regional lymph nodes in the armpit / axilla
o N 1: no metastasis to axilla nodes that can still be driven
o N 2: no metastasis to axilla KGB hard-driven
o N 3: there is metastasis to the lymph nodes above the collarbone (supraclavicula) or the internal mammary lymph nodes in the bone near the sternum
* M (metastasis), distant spread:
o M x: distant metastasis can not be assessed
o M 0: there is no distant metastasis
o M 1: there is distant metastasis
After each factor of T, N, and M obtained, the three factors are then combined and stage of cancer will be obtained as follows:
* Stage 0: T0 N0 M0
* Stage 1: T1 N0 M0
* Stage IIA: T0 N1 N1 M0/T1 M0/T2 N0 M0
* Stage IIB: T2 N1 M0 / T3 N0 M0
* Stage IIIA: T0 M0/T1 N2 N2 N2 M0/T2 M0/T3 M0/T2 N1 N2 M0
* Stage IIIB: T4 N0 M0 M0/T4 N1 N2 M0/T4
* Stage III C: Any T N3 M0
* Stage IV: Any T, Any N, M1
Genetic
DNA micro-arrays
DNA micro-array is a method that begins by comparing normal cells with cancer cells and see the differences that occur in genetic expression between two cell types. Although differences in genetic expression are not necessarily indicate the hallmark of oncogenes of cancer cells, but some researchers consider the group that some groups / clusters of genes have a tendency to leave a genetic imprint on other cells to occur the same genetic expression, called a genetic profile. Thus, the dynamics of functional genes and the genome can be observed as the process of transcription of mRNA, identification of binding domains of protein nucleic acid, single-nucleotide polymorphism analysis.
A number of genetic profiles has been proposed by various parties, some of which are:
* Genetic Profile of the American Society of Clinical Oncology that offers a classification based on CA 15.3, CA 27.29, CEA, perceiving the estrogen, progesterone perceiving, perceiving epidermal growth factor-2, urokinase plasminogen activator, plasminogen activator inhibitor 1. The use of the following categories as basis of diagnosis is also considered not enough; DNA / ploiditas with the use of flow cytometry, p53, cathepsin D, cyclin E, certain multiparameter assays, detection of micro-metastasis in bone marrow and tumor cell levels in the blood circulation.
* Profile genetic-called normal breast-like, basal, luminal A, luminal B and ERBB2 +.
* Subtypes based on the profile ESR1/ERBB2 ESR1 + / ERBB2-, ESR1-/ERBB2-, and ERBB2 +.
Perou-Sørlie intrinsic profile
From the viewpoint of histology, breast tumor cells is a complex network consisting of various types of cells besides cancer cells. To obtain the genetic profile of a tumor, note the typical genetic expression of each cell is the result of transcription of certain gene clusters, and then sought similarity clusters in other cells of different types.
On the intrinsic profile, found eight genetic clusters that is a variation of certain cells found in tumors.
1. Endothelial cells. A cluster of genes is a hallmark of the genetic expression of endothelial cells, such as CD34, CD31, von Willebrand factor, both endothelial cells from cultured HUVEC and HMVEC.
2. Stromal cells. The protein expression of stromal cells is a genetic clusters identified in advance and include several isomers of collagen
3. Normal breast cells as well as rich in adipose tissue with a genetic cluster includes the fatty-acid binding protein 4 and PPAR
4. B cells, leaving a trail of such genetic form of the protein immunoglobulin gene expression during infiltration and provide variation in genetic clusters as in the expression of cell culture RPMI-8226 multiple myeloma.
5. T cells also leave a genetic trail that an indication of infiltration activity. A geneteik clusters include cluster of differentiation and 2 subunits perceiving CD3 T cells found in MOLT-4 cells from the culture of childhood leukemia.
6. Makrofaga. A genetic clusters that appeared to be the hallmark of makrofaga / monocytes are the expression of CD68, acid phosphatase 5, chitinase and lysozyme.
There are two types of epithelial cells in this gland, namely basal cell or cell mioepitelial, and luminal epithelial cells. Many genes are only owned by one of these cell types and the rare genes that are owned by the two cells. Genetic clusters include basal cell keratin-5, keratin-17, integrin-4 and laminin. While the genetic clusters of luminal cells include transcription factors that are associated with perceiving such estrogen-binding protein GATA-3, X-box binding protein-1 and hepatocyte nuclear factor-3.
Panorama of Oncogenic
Classification according to oncogenic trajectory is divided into 4 subtypes called
* Luminal A that accompanied the perceiving expression of hormones, either estrogen, progesterone, or both, and without expression of HER-2 (English: human epidermal growth factor receptor 2). In luminal subtype A, occurs over-expression of proteins that play a role in the trajectory of fatty acid metabolism and cellular signal transduction path that uses steroids, especially through the expression of estrogen perceiving.
* Luminal B by the perceiving hormone +, HER-2 +.
* Triple negative with perceiving hormone -, HER-2 -.
* HER-2 over-expressing the hormone pengecerap -, HER-2 +.
Based on this classification, sampling results from 2544 cases in the United States, 73% found to suffer from the luminal subtype A, 12% of patients with luminal B, 11% were triple negative cancers and 4% is the kind of HER-2 over-expressing.
Several other experts added subtypes such as;
* Basal-like system with excess expression of proteins that play a role in proliferation and differentiation of cells, the trajectory of p21 and signal transduction in the cell cycle at the checkpoint between the G1 phase and S phase
* Basal trajectory A with ETS and the BRCA1 gene.
* Basal B with the track mesenchymal cells and / or stem cells / progenitor cells
Clinical symptoms
Clinical symptoms of breast cancer can be:
Lumps in the breast
Usually a painless lump in the breast. The lump was initially small, the longer it will be even greater, then attached to the skin or cause changes in the breast skin or nipple.
Erosion or eczema nipple
Skin or nipple had become interested in (retraction), pink or brownish until the edema until the skin looks like orange peel (peau d'orange), contract, or arising out ulcers (ulcers) in the breast. Ulcers that the longer the greater and deeper so that it can destroy the entire breast, often foul-smelling, and bleed easily. Other features include:
* Bleeding on the nipple.
* Pain or tenderness in the new generally arise when the tumor was large, had ulcers arise, or when it appears metastases to the bones.
* Then comes enlarged lymph nodes in the armpits, swelling (edema) on the arm, and the spread of cancer throughout the body (Handoyo, 1990).
Advanced breast cancer is very easily recognizable by knowing operbilitas Heagensen following criteria:
* There is extensive edema of the breast skin (over 1 / 3 area of breast skin);
* Presence of satellite nodules on the skin of the breast;
* Type of breast cancer mastitis karsinimatosa;
* There parasternal model;
* There is a supraclavicular nodule;
* Of the edema arm;
* Presence of distant metastases;
* And there are two of the signs of locally advanced, namely skin ulceration, skin edema, skin fixed to the thoracic wall, axillary lymph node diameter is 2.5 cm, and axillary lymph node attached to one another.
Discharge (Nipple discharge)
Nipple discharge is a discharge from the nipple spontaneously and not normal. The liquid that comes out is called normal if it occurs in women who are pregnant, breastfeeding and contraceptive pill users. A woman should be wary if the nipple discharge of bloody watery liquid with red or brown, out on his own without having to massage the nipples, continues, only in one breast (unilateral), and liquids other than breast milk.
Factors causing
Risk factors
According Moningkey and Kodim, the specific causes of breast cancer is still unknown, but there are many factors that are estimated to have an influence on the occurrence of breast cancer include:
1. Reproductive factors: reproductive characteristics associated with risk of breast cancer is nuliparitas, menarche at a young age, menopause at an older age, and first pregnancy at older age. The main risk of breast cancer is increasing age. It is estimated, the period between the occurrence of first menstruation to the age at first pregnancy is a window of initiation of breast cancer progression. Anatomically and functionally, the breasts will atrophy with age. Less than 25% of breast cancers occur in the period before the onset of menopause so I assume that the tumor occurred well before the occurrence of clinical changes.
2. The use of hormones: estrogen hormone associated with the occurrence of breast cancer. Report from the Harvard School of Public Health states that there is a significant increase in breast cancer in users of estrogen replacement therapy. A meta-analysis stated that although there is no risk of breast cancer in users of oral contraceptives, women taking these drugs for a long time have a higher risk to develop breast cancer before menopause. The cells are sensitive to hormonal stimulation may experience changes in benign or become malignant degeneration .
3. Fibrocystic Disease: In women with adenosis, fibroadenoma, and fibrosis, there is no increased risk of breast cancer. In hiperplasis and papilloma, slightly increased risk of 1.5 to 2 times. While in atypical hyperplasia, the risk increases to 5 times.
4. Obesity: There is a positive relationship between body weight and body shape with breast cancer in postmenopausal women. A variation on the frequency of these cancers in Western countries and non-Western as well as the frequency changes after migration indicates that there is influence of diet on the occurrence of this malignancy.
5. Consumption of fat: Fat consumption is estimated as a risk factor for breast cancer. Willett et al. done for 8-year prospective study on fat and fiber consumption in relation to risk of breast cancer in women aged 34 to 59 years.
6. Radiation: Exposure to ionizing radiation during or after puberty increases the risk of breast cancer. Of the few studies conducted concluded that the risk of radiation-related cancer linearly with dose and time of exposure age.
7. Family history and genetic factors: Family history is an important component in the history of the patient to be carried out screening for breast cancer. There is an increased risk of malignancy in women whose family had breast cancer. In genetic studies found that breast cancer associated with specific genes. If there is BRCA 1, which is a breast cancer susceptibility gene, the probability of occurring breast cancer by 60% at age 50 and by 85% at age 70 years. Age factor is very influential -> about 60% of breast cancers occur in the age of 60 years. The biggest risk 75 years of age.
Genetic Factors
Breast cancer can occur because of some genetic factors derived from parent to child. Genetic factors in question is the presence of mutations in several genes that play an important role in the formation of breast cancer gene in question is some of the genes are oncogenes and tumor suppression gene that nature.
Pensupresi tumor gene plays an important role in the formation of breast cancer include BRCA1 and BRCA2 genes.
Cancer Treatment
There are several breast cancer treatment whose application depends a lot on the stage of clinical disease , namely:
Mastektom
Mastectomy is the surgical removal of the breast. There are three types of mastectomy (Hirshaut & Pressman, 1992):
* Modified Radical Mastectomy, the surgical removal of the entire breast, breast tissue in the sternum, collarbone and ribs, and lump around the armpit.
* Total (Simple) Mastectomy, the surgical removal of the entire breast, but not the glands in the armpit.
* Radical Mastectomy, the surgical removal of part of the breast. Usually called a lumpectomy, which is only on the removal of tissue containing cancer cells, not the entire breast. This operation is always followed by the provision of radiotherapy. Lumpectomy is usually recommended in patients with large tumors less than 2 cm and located at the edge of the breast.
Radiation
Radiation / radiation is the process of irradiation on the area affected by cancer by using X-rays and gamma rays are aimed at killing cancer cells remaining in the breast after surgery (Denton, 1996). The effect of this treatment the body becomes weak, poor appetite, skin color around the breast to be black, as well as hemoglobin and leukocytes tended to decline as a result of radiation.
Chemotherapy
Chemotherapy is the process of giving anti-cancer drugs or sitokina in the form of pills or capsules or liquid through the infusion aimed at killing the cancer cells through a mechanism of chemotaxis. Not only in breast cancer cells, but also throughout the body (Denton, 1996). Effects of chemotherapy is the patient experiencing nausea and vomiting and hair loss due to the influence of drugs given during chemotherapy.
Acid is a bisphosphonate compound inhibiting osteoclast activity and bone resorption are often used to fight osteoporosis induced by ovarian suppression, hypercalcemia, and abnormalities of bone metabolism, demonstrated effectiveness for lowering breast cancer cell metastasis to bone. Although bisphosphonates are generally acid intake can be tolerated body, long-term use can cause side effects such as osteonecrosis and declining kidney function.
CT can induce breast cancer cells to produce cAMP and inhibit cancer cell growth. The molecule cAMP is formed from the expression of the CT connected perceiving adenylate cyclase by at least one guanine nucleotide-binding protein. CAMP response to CT can be decreased when cells terinkubasi mitogenic compounds in the form of 17beta-estradiol and EGF, and increased incubation as growth inhibitory compounds such as tamoxifen and 1,25 (OH) 2D3; as well as oligonucleotides and proto-oncogene c-myc. However, the use of tamoxifen increases the risk of endometrial polyps, hyperplasia and cancer, through the mechanism of adrenomedullin.
Production of cAMP response is strong, not found in compounds other than CT. Adenylate cyclase effector compounds such as forskolin and compound beta-adrenergic receptor agonists such as isoproterenol produces only a little production of cAMP.
In cells MDA-MB-231, CT would induce c-Raf phosphorylation at position 259 Serina through the trajectory of protein kinase A and lead to inhibition of phosphorylation of ERK1 / 2 is necessary for the survival of cells MDA-MB-231, and inhibit the expression UPA mRNA required cells MDA-MB-231 for the invasion and metastasis. However calcitonin had no effect signifan to inhibit proliferation of MCF-7 cells. Apoptosis cells MDA-MB-231 also induced by lipoic acid, which inhibits phosphorylation of AKT and AKT mRNA, the activity of Bcl-2 and Bax proteins, MMP-9 and MMP-2, and increased activity of caspase-3.
Prevention Strategies
In principle, prevention strategies are grouped into three major groups, namely the prevention of the environment, the host, and milestones. Almost every epidemiologist agree that the most effective prevention for the incidence of non-communicable diseases is health promotion and early detection. Similarly, in breast cancer, prevention is carried out among others:
Primary Prevention
On primary prevention of breast cancer is one form of health promotion because it is done in people who are "healthy" through efforts to avoid exposure to various risk factors and implement healthy lifestyle. Prevention this primer can also be a breast self-examination (breast self-examination) is done routinely so they can minimize risk factor for breast cancer.
Secondary Prevention
Secondary Prevention conducted on individuals who are at risk for developing breast cancer. Every normal woman and have a normal menstrual cycle is the population at risk of breast cancer. Secondary prevention was done by early detection. Several methods of early detection continues to experience growth. Screening through mammography is claimed to have accuracy of 90% of all breast cancer patients, but continuous exposure to mammography in healthy women is one risk factor for breast cancer. Therefore, screening with mammography can still be implemented by several considerations, among others:
* Women who have reached age 40 are encouraged to do cancer risk assessement survey.
* In women with risk factors received a referral for mammography done every year.
* Women normally receive a referral mammography every 2 years until they reach age 50.
Foster and Constanta found that breast cancer mortality by less in women who perform BSE (Breast Self-Examination) than those without. Although the sensitivity of BSE for detecting breast cancer only 26%, when combined with mammography is early detection sensitivity to 75%
Tertiary Prevention
Tertiary prevention is usually directed at individuals who have been positive breast cancer. Proper treatment of breast cancer patients according to the stage is going to be able to reduce notes and prolong survival. Tertiary prevention is crucial to improving patient quality of life and prevent complications of the disease and continue treatment. Measures of treatment may include surgery, although no effect on patient survival. If the cancer has distant metastatic disease, chemotherapy with sitostatika action. At a certain stage, the treatment provided was only for symptomatic and are encouraged to seek alternative treatments.
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