presentation_1_-4m03.pptx

Figure 1 - Imaging of breast cancer. Arrow indicating location of possible breast cancer. (Barry et al., 2012)

The breast is an organ that is primarily composed of adipose tissue that is found on the chest region, situated right in front of the pectoralis major muscle. The organ is found in both males and females, but have no functional purpose in males. The breast in females has a specialized function which is the production of milk for lactation. The breast anatomy is composed of 2 components the epithelial component, the lobules where milk is made, and the duct component, which connects the lobules to the external area of the nipple. In male breast anatomy, the ductal component is shunted creating blind ducts, which differentiates them from female breasts.

Breast cancer is the result of the abnormal division of breast cells within the organ. Breast cancer can be an inherited or sporadic cancer, but the most common type of genes involved are the BRCA1 and BRCA2 genes. The cells within the breast can create a tumor at the primary site in the breast. Breast cancer normally develops from the ductal tissues which is known as ductal carcinomas or lobular tissues which is known as lobular carcinomas. Breast cancer has a high potency of metastasizing to other nearby tissues.

Within Canada, 24,400 women and 210 men are diagnosed per year, with over 5,000 women and 60 men dying of disease. Globally, breast cancer in women accounts to 25% of all cancer cases, making it one of the largest sector of cancer in women (Boyle & Levin, 2008). Moreover, breast cancer is more common in developed countries compared to developing countries. Most cases of breast cancer are not reported because males or females refuse to report it to doctors, feminizing syndrome, or it could be simply caught too late (da Silva, 2015).

The five most common signs of breast cancer are as follows;

1. A new lump

• A new lump or thickening in the breast or armpit area

2. Nipple Change

• A newly inverted [pulled in] or retracted nipple

3. Skin Change

• A change in the skin of the breast, areola or nipple e.g. color, dimpling, puckering, or reddening

4. Shape Change

• A change in the breast shape or size

5. Nipple Discharge

• A discharge from the nipple that occurs without squeezing

Figure 2 - How breast cancer can look like through the use of lemons. (KNOW YOUR LEMONS CAMPAIGN/WORLDWIDE BREAST CANCER ORGANIZATION, 2016)

Breast cancer is the most common malignant cancer in females, comprising of 18% of all female cancers. An estimated 1.4 million cases of breast cancer related incidents are recorded per year globally. Out of these 1.4 million cases, 460, 000 are confirmed deaths (Tao, 2015). Projecting these incident rates to 2050, it is estimated that the cases will increase to 3.2 million cases recorded per year, more than double of the current incident rates (Tao, 2015). Incident rates are determined to continue growing throughout the oncoming years (McPherson, 2000).

However, in parallel to the rising incidence rates, mortality rates have declined since the 1990’s (Li, 2010). This is merely due to the cancer detecting technology that has been introduced, such as screening mammography. Screen tests has allowed doctor’s to detect cancer at early stages, increasing incident rates, and treat them before the aggressive stages, declining mortality rates (Li, 2010).

Growing research in the cancer field has brought among greater technology and therapies to target and destroy the cancer, but unfortunately this is also leading to a discrepancy in some geographical distributed regions in reference to global incidence and mortality numbers (DeSantis, 2015). Particularly, low income countries have been continuing to show an increase in incidence and mortality rates. These countries do not have the means to employ screening technologies and therapies due to the high costs. Once primarily known as a disease of western women, now more than half of breast cancer incident cases and mortality cases are recorded in economically developing countries. (DeSantis, 2015)

Figure 3 - DeSantis, C., Bray, F., Ferlay, J., Lortet-Tieulent, J., Anderson, B., & Jemal, A. (2015). International Variation in Female Breast Cancer Incidence and Mortality Rates. Cancer Epidemiology Biomarkers & Prevention, 24(10), 1495-1506. http://dx.doi.org/10.1158/1055-9965.epi-15-0535

In terms of age, studies in the United Kingdom have shown highest incident rates are recorded among females within the age of 50-64 years (McPherson 2000). This may be due to standardized annual screening tests implemented by the government which are required to be completed. Additionally, breast cancer does cause the greatest deaths in the ages of 40-50 years, this may be due to gene reactivity or changes in female systems occurring during these middle ages (McPherson, 2000)

Some related factors to breast cancer incidences are genetic predisposition of the cancer gene, mutations in the DNA leading to the cancer cell production and proliferation from radiation, geographical variation which ties into the differences in genetic makeup of females living in particular regions or are exposed to carcinogens in their environments, lifestyle, and female bodily cycles such as menopause which causes significant changes in the body (McPherson, 2000). Some preventative measures may be taken such as dietary intervention. These changes may be difficult for some to adapt due to cultural bringing up of an individual. One particular key point in terms of dietary factors includes a study which proposes if a female gains 10-20 pounds more from her weight at the age of 18, this may be associated with an increase of risk to breast cancer (McPherson, 2000). Other preventative measures include hormonal control which tackles the naturally occurring cycles in the female body from getting out of control (McPherson, 2000).

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Figure 1: Asthma Risk Factors

Prior to being diagnosed with breast cancer there are ways to test for an individual’s genetic risk factors for developing the disease. Majority of inherited cases of breast cancer is a result of mutations within the BRCA1 or BRCA2 genes. BRCA1 is found on chromosome 17, whereas BRCA2 is found on chromosome 13 (Radford & Zehnbauer, 1996). This is an important gene to consider as an individual only needs one mutated copy in order to possess increased chances of developing breast cancer. If one parent has this mutation, their offspring will automatically have a 50% chance of inheriting it and developing specific cancers (Radford & Zehnbauer, 1996). Un-mutated BRCA genes produce tumor suppressor proteins that aid in the repair of damaged DNA (Radford & Zehnbauer, 1996). As a result, when mutations occur within either BRCA gene, the damaged DNA is left un-repaired, resulting in higher chances of future cancer development.

Though majority of breast cancer cases are sporadic, approximately ten percent of cases result from an inherited autosomal dominant mutation within the BRCA genes (Radford & Zehnbauer, 1996). However, once a mutation is inherited, there is a 65-85% chance that an individual will develop breast cancer by the time they are 70 years old (Radford & Zehnbauer, 1996). Genetic screening options are available with the purpose of identifying individuals at risk of developing certain cancers within their lifetime. There are two main methods used when screening for inherited breast cancer-causing mutations. The first form of genetic screening searches for every known mutation that is linked to cancer. This is done by collecting a sample of DNA, typically a buccal sample, and examining it for cellular mutations. The second method collects a DNA sample in a similar way, however it also requires the collection of DNA from at least four family members who are known to have a BRCA mutation (Radford & Zehnbauer, 1996). By doing this, the test screens for those particular mutations that are currently present within the family. Once the tests have been completed an individual is then identified as being positive or negative. A positive test implies that they possess a known BRCA mutation (Radford & Zehnbauer, 1996). However, it is important to understand that carrying a mutation does not necessarily mean an individual will develop the disease, it just informs them that they have an increased chance of future development.

There are also a variety of indirect examinations to test for the presence of breast cancer without collecting DNA samples. One such test is a mammography. This type of screening makes use of breast imaging via low-dose X-rays (Canadian Cancer Society, 2017). Using this technique it is possible to detect the presence of breast cancer at its earliest stages, when it is most treatable and mortality rates are low. During this procedure, each breast is individually compressed by parallel plates. In doing so, the breast thickness is reduced, making it easier to recognize abnormal masses. X-rays are then used to create images for examination (Canadian Cancer Society, 2017). Additionally, in the province of Ontario it is recommended that females between the ages of 50-74 get mammograms done every two years, in order to detect early development of breast cancer.

A second procedure is a breast biopsy which is used to remove patches of tissue or fluid from abnormal lumps within the breast. There are three types of breast biopsies when trying to discover the presence or absence of breast cancer. The first is fine needle aspiration. This is the least commonly used method out of the three with regards to breast cancer. However, this method is used when a lump is easily reachable and expected to be fluid-filled (Ballo & Sneige, 1996). The extremely thin needle allows for extraction of the fluid to be used for examination. The second method is core needle biopsy. This method makes use of a slightly larger, hollow needle. Using this technique technicians are able to remove layers of tissue from suspicious areas within the breast in order to determine how far cancer has penetrated (Ballo & Sneige, 1996). The final method is called surgical biopsy. This is done by making an incision, ranging from one to two inches on the breast (Ballo & Sneige, 1996). Following this, part or all of the abnormal mass is removed, along with a small amount of surrounding tissue. All three methods are used to determine if cancer cells are present in abnormal masses within the breast.

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Breast Cancer is similar to other cancers in which abnormal cell growth can potentially invade and spread to other areas of the body. In normal cell growth, cells can divide as necessary and have functioning signals that can stop cell division. These cells stay attached and localized in their respective sites and do not spread or invade other areas. Normal cells can also undergo programmed cell death, which keeps a balance in the cell population and discards unnecessary cells (Hartwell & Kastan, 1994).

The P13K pathway is an example of one of the most important pathways that protect cells by controlling functions such as cell growth, differentiation, motility, survival, and proliferation. P13Ks are lipid kinases that phosphorylate phosphoinositides. The P13Ks involved in breast cancer are Class 1A, which are comprised of a regulatory subunit (p85) and a catalytic subunit (p110). The activation of the P13K is initiated from growth factor or ligand binding to its respective receptor tyrosine kinase (RTK). These receptors contain two important growth factor receptors; the human epidermal growth factor receptor (HER) family and the insulin-like growth factor 1 receptor (IGF-1R). Once activated by a receptor, the P13K heterodimer interacts with a portion of the p85. This binding removes the inhibitory effect of p85 on p1110 rendering the P13K pathway active. The activation leads to a cascade of events downstream of the pathway, resulting in diverse functions such as cellular metabolism, proliferation, differentiation and survival (Liang & Slingerland, 2003).

In breast cancer this pathway is aberrantly hyperactive, as shown in Figure __. This results from mutations in various parts of the pathway but most predominantly in PIK3CA, which encodes for the catalytic p110a subunit. Mutations in these promote downstream signaling elements such as Akt that increase enzymatic function. The overexpression of p110a subunit, therefore leads to robust activation of the pathway (Berns et al., 2007). P13K pathway also involves tumor suppressors such as PTEN, which turn off the pathway and induce cell death. However, in cases such as breast cancer, the PTEN protein may be mutated and unable to turn off the pathway. Therefore, there is excessive cell proliferation and the cell does not undergo programmed cell death. In this case, low expression of PTEN leads to excessive cell growth (Depowski, Rosenthal, & Ross, 2001).

Figure 2 - PTEN Pathway and Mutations Retrieved from: http://theoncologist.alphamedpress.org/content/16/suppl_1/12/F1.expansion

The ErbB is a family of receptor tyrosine kinases, which include the Her2 (ErbB2) receptor-tyrosine-protein kinase. Both the P13K/AKT pathway and Ras-Raf-MAPK pathway are important signalling routes for the ErbB protein. In normal cell activity, the ErbB protein forms homodimers and heterodimers upon activation by growth factor ligands. Upon dimerization these proteins become autophosphorylated and act as binding sites for intracellular signal activators. This triggers a signal cascade leading to increased cell proliferation and inhibition of apoptosis (cell death). Mutation in the HER2 gene leads to amplification of this oncogene and excessive ErbB signalling. Therefore, this increased signalling leads to aberrant cell proliferation and increased inhibition of cell apoptosis (Mitri, Constantine, & O’Regan, 2012).

Figure shows the various types of abnormalities that can result from abnormal cell growth. Ductal hyperplasia contains lesions in the breast that are not cancerous but have active growth and division in the breast tissue cells. Atypical Ductal Hyperplasia and Ductal Carcinoma In Situ (DCIS) occurs when breast tissue is beginning to take an abnormal appearance, however the abnormal cells are still localized in within the tissue. In DCIS-microinvasion and Invasive ductal cancer, the excessive cell growth spreads outside of the tissue and invades other areas of the body (Hüsemann et al., 2008).

Figure 2 - Type of Abnormalities. (Da Silva, R. (2015) Module 3 Lecture 2: Breast Cancer[PowerPoint Slides]. Retrieved from McMaster University Health and Disease)

The spread of the tumour varies with different stages in breast cancer. Usually, the least progressive is when atypical cells are in the breast tissue and there are no signs of spread to lymph nodes. As the tumour size increases it begins to spread to lymph nodes and there is metastases in axillary lymph nodes. From here the tumours of any size may spread into the skin, chest wall, and eventually the cancer spreads to other organs and tissues (Hüsemann et al., 2008).

The cancer cells are able to spread to various areas of the body by penetrating the extracellular matrix and blood vessels. Cells are constrained in their respective organs by cell-cell adhesion and basement membrane. However, cancer cells can penetrate the basement membrane by using invadopodia. Invadopodia is the process in which cells form actin-rich protrusions in the plasma membrane and subsequently degrade the extracellular matrix. Genes involved in these protrusions and invasions are upregulated in malignant cancer cells, allowing increased cell invasion and motility. This way, some cells contained in the tumour can separate from their parent mass and enter vascular and lymphatic circulation (Linder, 2007).

At its current state, there has yet to be an established permanent cure to individuals suffering from asthma. Fortunately, various management techniques are available and can be implemented in order to help alleviate the various symptoms associated with the disease. The primary suggestion asthmatic patients are recommended to do is to avoid any of the mentioned irritants involved in triggering an inflammatory response of the airway. In addition to avoiding any potential allergens, medication is available for both short-term and long-term relief. While short-term medication can provide immediate relief to counteract the constriction of the airway, long-term medication can be taken in the form of a daily supplement to aid in controlling against any future aggravation (Kuna & Kuprys, 2002).

A common short-term therapeutic can be found in the form of bronchodilators such as Ventolin. Bronchodilators are classified as beta-agonists, which seek target beta-adrenergic G-protein coupled receptors (GPCRs) of the bronchial smooth muscle (Kuna & Kuprys, 2002). Upon binding to these membrane-bound receptors, surrounding adenyl cyclase and ATP interact, leading to the production of cyclic-AMP (cAMP) and a subsequent cascading release into the cell. With the function of cAMP being a secondary messenger for enzyme-catalyzed processes within the cell, the relaxation of the smooth muscle cells acts further downstream in this reaction pathway (Kuna & Kuprys, 2002). Normally requiring epinephrine to produce smooth muscle relaxation, Ventolin acts as mimic to adrenaline due to both its conformation and structure, allowing it to produce the same intended result when taken by an asthmatic patient (Kuna & Kuprys, 2002). Another alternative to Ventolin is another inhaler known as Formoterol, which is better known for its more long-term viability. Taking advantage of a mechanism similar to Ventolin, the active ingredients in Formoterol allow the drug to remain at the level of the cell-membrane for an extended period of time (Pauwels et al., 1997). In addition to allowing the bronchodilation of the patient, Formoterol is also able to bind to beta2-adrenergic receptors located on the membrane of mast cells. With the binding of Formoterol to beta2-adrenergic receptors, the release of histamine, an inflammatory agent released by cells in response to any allergic response, is negatively inhibited (Pauwels et al., 1997). With the inhalation of Formoterol on a regular basis, individuals suffering from asthma will be able to relieve themselves of both bronchoconstriction and a hypersensitive response due to any irritants over a long term period.

Figure 5: Ventolin, a bronchodilator used in providing short-term relief from symptoms of asthma

A different type of medication used to treat asthma is anti-inflammatory medication. These anti-inflammatory drugs are corticosteroids such as Budesonide and alike bronchodilators, this form of drug is taken by inhalation. Budesonide reaches the target cells within one minute of inhalation and closes vascular micro leaks via vasoconstriction of the bronchi. Relaxation of the bronchial smooth muscles is experienced after 2-3 hours due to the activation of transcription factors, which increases the number of accessible beta-2 receptors (Pauwels et al., 1997). A new type of therapeutic being tested is a combination therapy involving both bronchodilators and anti-inflammatory pathways. Symbicort is a prime example of this combination medication and its use displayed that the two mechanisms have synergistic effects. Since budesonide leads to an increased number of expressed beta-2 adrenergic receptors, there are more total receptors for formoterol to bind to. In addition to this, the binding of formoterol to these beta-2 receptors increases the activity of budesonide, leading to an increased amount of anti-inflammation (Bryan et al., 2000).

Figure 6: Symbicort, used in combination drug therapy, is efficient due to the synergistic effects provided when using both bronchodilators and anti-inflammatory medication in tandem.

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