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group_1_presentation_1_-_breast_cancer [2017/10/05 19:10] mehtak3 [Etiology] |
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| ======= Breast Cancer ======= | ======= Breast Cancer ======= | ||
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| + | Powerpoint file: {{:a-look-inside-breast-cancer-1.pptx|}} | ||
| ===== Introduction ===== | ===== Introduction ===== | ||
| - | Breast cancer is the cancer associated with an uncontrollable division of cells in the breast tissues. (WORKING) | + | Breast cancer is the cancer associated with an uncontrollable division of cells in the breast tissues. It is attributed by abnormal cell growth in beginning the ducts and lobules. Although both males and females can be diagnosed, breast cancer is more prevalent in women on a much larger scale. 1 in 8 women will be diagnosed in their lifetime therefore both breast cancer research is vital for treatment of the diseases. Breast cancer is attributed to four different stages. These stages are defined by both the size of the tumour and the spread of the cancer to tissues, muscles, and organs. Symptoms of the disease can include a lump in the breast, skin dimpling, and red patches on the skin. |
| ===== Etiology ===== | ===== Etiology ===== | ||
| **Breast Cancer Aetiology** | **Breast Cancer Aetiology** | ||
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| ===== Epidemiology ===== | ===== Epidemiology ===== | ||
| - | {{ :screen_shot_2017-10-02_at_5.24.40_pm.png |}} **Figure 1:** | + | {{ :screen_shot_2017-10-02_at_5.24.40_pm.png |}} **Figure 1:** This chart shows the risk of developing breast cancer at different ages divided in ten year intervals. Risk of breast cancer increases by age |
| === Incidence: === | === Incidence: === | ||
| - | The greatest incidence is found in European countries, followed by America and Canada. Rates of breast cancer are significantly lower in African countries. According to WHO, there were over 508 000 deaths around the globe in 2011. | + | The greatest incidence is found in European countries, followed by America and Canada. Rates of breast cancer are significantly lower in African countries. According to WHO, there were over 508 000 deaths around the globe in 2011 <sup>[4]</sup>. |
| === Distribution === | === Distribution === | ||
| - | Breast cancer affects women around the globe. Death rates are lower in developed countries as more treatment options are available in these regions. The number of cases is steadily increasing in developing countries where treatment and cancer tests are not as readily available. According the American Cancer society, it is projected that there will be 1.6 million new cases of breast cancer in the world. | + | Breast cancer affects women around the globe. Death rates are lower in developed countries as more treatment options are available in these regions. The number of cases is steadily increasing in developing countries where treatment and cancer tests are not as readily available <sup>[24]</sup>. According the Canadian Cancer society, it is projected that there will be 1.6 million new cases of breast cancer in the world <sup>[6]</sup>. |
| === Control of disease === | === Control of disease === | ||
| - | There are a variety of methods to treat breast cancer (see more in the treatment section). They can generally be divided into invasive and non-invasive. Moreover, continuous research is done by different organizations such as the Breast Cancer organization. | + | There are a variety of methods to treat breast cancer (see more in the treatment section) <sup>[4]</sup>. They can generally be divided into invasive and non-invasive <sup>[4]</sup>. Moreover, continuous research is done by different organizations such as the Breast Cancer organization <sup>[4]</sup>. |
| === Survival rates === | === Survival rates === | ||
| - | Although survival rates are increasing, low-income countries are still suffering from lack of available resources to diagnose and treat cancer. Survivability rates have reached over 80% in North America but still remain below 40% in developing and low income countries. | + | Although survival rates are increasing, low-income countries are still suffering from lack of available resources to diagnose and treat cancer. Survivability rates have reached over 80% in North America but still remain below 40% in developing and low income countries <sup>[5]</sup>. |
| - | Detection and treatment of breast cancer in earlier stages show an increase in success rates. In 2014, over 236, 968 women were affected in the US and 2141 men and led to 41, 211 deaths in women and 456 deaths in men. | + | Detection and treatment of breast cancer in earlier stages show an increase in success rates. In 2014, over 236, 968 women were affected in the US and 2141 men and led to 41, 211 deaths in women and 456 deaths in men <sup>[5]</sup>. |
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| ===== Anatomy and Physiology ===== | ===== Anatomy and Physiology ===== | ||
| - | Breasts are organs that have a specialized function that is the production of milk for lactation. The breast is made up of lobes, ducts, fat, connective tissues, and glands. Female breasts have specialization as both lobes and ducts are connected to allow for secretion of nutrients. The male breasts however only have the ducts that have a blunt end, and the ducts do not connect to lobes. Both female and male breasts sit atop the pectoralis muscle (National Cancer Institute, 2015). | + | Breasts are organs that have a specialized function that is the production of milk for lactation<sup>[34]</sup>. The breast is made up of lobes, ducts, fat, connective tissues, and glands. Female breasts have specialization as both lobes and ducts are connected to allow for secretion of nutrients<sup>[34]</sup>. The male breasts however only have the ducts that have a blunt end, and the ducts do not connect to lobes<sup>[34]</sup>. Both female and male breasts sit atop the pectoralis muscle<sup>[34]</sup>. |
| - | {{ :screen_shot_2017-10-02_at_5.04.59_pm.png |}} **Figure 5:** | + | {{ :screen_shot_2017-10-02_at_5.04.59_pm.png |}} **Figure 5:** Compares the male breast anatomy and the female breast anatomy. |
| - | The breasts are connected to the blood and lymph vessels. The lymph vessels collect and move the lymph fluid away from the breast into lymphatic tissue (lymph nodes) around the breast. The lymph vessels and lymph nodes compose the lymphatic system of the breast. The axillary lymph nodes are under the arm, and are divided into three levels include<sup>[4]</sup>: | + | |
| + | The breasts are connected to the blood and lymph vessels. The lymph vessels collect and move the lymph fluid away from the breast into lymphatic tissue (lymph nodes) around the breast<sup>[6]</sup>. The lymph vessels and lymph nodes compose the lymphatic system of the breast<sup>[6]</sup>. The axillary lymph nodes are under the arm, and are divided into three levels include<sup>[6]</sup>: | ||
| * Level I is low axilla, which is along the outer border of the pectoralis minor | * Level I is low axilla, which is along the outer border of the pectoralis minor | ||
| * Level II is mid axilla, beneath the pectorals minor | * Level II is mid axilla, beneath the pectorals minor | ||
| * Level III is high axilla, along the inner border of pectorals minor | * Level III is high axilla, along the inner border of pectorals minor | ||
| - | When breast cancer spreads, it spreads to level I lymph nodes first, followed by level II, and level III (Canadian Cancer Society, 2017). | + | When breast cancer spreads, it spreads to level I lymph nodes first, followed by level II, and level III<sup>[6]</sup>. |
| + | |||
| + | {{ :screen_shot_2017-10-02_at_5.51.59_pm.png |}} **Figure 6:** Illustrates the axillary lymph nodes : level I, level II, and level III. | ||
| - | {{ :screen_shot_2017-10-02_at_5.51.59_pm.png |}} **Figure 6:** | ||
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| - | |||
| ===== Stages of Breast Cancer ===== | ===== Stages of Breast Cancer ===== | ||
| The stage of breast cancer is determined from testing the tumour tissue, lymph nodes and organs surrounding the breast. Non-invasive techniques such as image testing and invasive techniques such as biopsies can help determine the spread of the cancer and help define the stage the cancer is in.{{ :screen_shot_2017-10-02_at_11.06.18_pm.png |}} **Figure 7:** | The stage of breast cancer is determined from testing the tumour tissue, lymph nodes and organs surrounding the breast. Non-invasive techniques such as image testing and invasive techniques such as biopsies can help determine the spread of the cancer and help define the stage the cancer is in.{{ :screen_shot_2017-10-02_at_11.06.18_pm.png |}} **Figure 7:** | ||
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| === Stage 0: Carcinoma In Situ Stage=== | === Stage 0: Carcinoma In Situ Stage=== | ||
| - | There is abnormal but non-invasive cellular growth in the ducts, lobule, or nipple region. Generally clinical breast exams or mammograms are recommended followed by a tamoxifen hormone therapy | + | There is abnormal but non-invasive cellular growth in the ducts, lobule, or nipple region <sup>[44]</sup>. Generally clinical breast exams or mammograms are recommended followed by a tamoxifen hormone therapy <sup>[44]</sup> |
| === Stage 1 === | === Stage 1 === | ||
| - | The cancer is found and contained in the regions where abnormal cells began to grow. If the cancer is stage 1a, the tumour is less than 2cm in size and has not spread to lymph nodes. If the cancer is in stage 1b, the cancer has moved to the lymph nodes but is less than 0.2-2mm in size. | + | The cancer is found and contained in the regions where abnormal cells began to grow <sup>[44]</sup>. If the cancer is stage 1a, the tumour is less than 2cm in size and has not spread to lymph nodes <sup>[44]</sup>. If the cancer is in stage 1b, the cancer has moved to the lymph nodes but is less than 0.2-2mm in size <sup>[44]</sup>. |
| === Stage 2 === | === Stage 2 === | ||
| - | The cancer continues to grow but remains either in the breast or has extended a little beyond the lymph nodes. Stage 2a means the tumour is either less than 2cm but has crossed less than 4 auxiliary lymph nodes or the tumour is between 2-5cm in size but has not spread towards the lymph nodes. Stage 2b can be characterized by the size of the cancer being between 2-5cm in size spreading into the lymph nodes or the tumour being about 5cm but has remaining stationary. | + | The cancer continues to grow but remains either in the breast or has extended a little beyond the lymph nodes <sup>[44]</sup>. Stage 2a means the tumour is either less than 2cm but has crossed less than 4 auxiliary lymph nodes or the tumour is between 2-5cm in size but has not spread towards the lymph nodes <sup>[44]</sup>. Stage 2b can be characterized by the size of the cancer being between 2-5cm in size spreading into the lymph nodes or the tumour being about 5cm but has remaining stationary <sup>[44]</sup>. |
| === Stage 3 === | === Stage 3 === | ||
| - | The breast cancer has now spread beyond the region of the original tumour growth and is beginning to affect muscles and lymph nodes beyond the original site. In stage 3a the tumour is growing beyond 5cm in size. There are also small clusters of cancerous cells found in the lymph node region. Otherwise, the tumour is larger than 5cm and spreading to lymph nodes and nearby regions like the breastbone or under the arm. In stage 3b, the tumour can grow to any size as it spreads and invades of the skin near the breast and chest walls. | + | The breast cancer has now spread beyond the region of the original tumour growth and is beginning to affect muscles and lymph nodes beyond the original site <sup>[44]</sup>. In stage 3a the tumour is growing beyond 5cm in size. There are also small clusters of cancerous cells found in the lymph node region. Otherwise, the tumour is larger than 5cm and spreading to lymph nodes and nearby regions like the breastbone or under the arm <sup>[44]</sup>. In stage 3b, the tumour can grow to any size as it spreads and invades of the skin near the breast and chest walls <sup>[44]</sup>. |
| === Stage 4 === | === Stage 4 === | ||
| - | This is considered the most dangerous stage, as there is no treatment to cure the cancer. The cancer has spread to other regions around the body and has metastasized into regions of the brain, bones, liver, and lungs. Treatment can only prolong the individual’s lifespan. | + | This is considered the most dangerous stage, as there is no treatment to cure the cancer <sup>[44]</sup>. The cancer has spread to other regions around the body and has metastasized into regions of the brain, bones, liver, and lungs <sup>[44]</sup>. Treatment can only prolong the individual’s lifespan. |
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| **BCRA Gene** | **BCRA Gene** | ||
| - | The breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are tumour suppressor genes, and translational protein products expressed in all humans (A1). The specific locality of BRCA1 and BRCA2 gene is on chromosome 13 and 17, respectively (A2, A3). Moreover, the significance of such genes is predominantly due to the associated lifetime risk for breast cancer (BC) when mutations are present. This is evidently shown through a prospective cohort study by Kuchenbaecker et al. which revealed the cumulative BC risk to age 80 years to be 72% for BRCA1 and 69% for BRCA2. Additionally, further data has shown a rapid increase in BC incidence from adulthood until ages 30-40 for BRCA1, and until ages 40-50 for BRCA2. However, past the upper-limit for the peak-incidence of each respective gene, the frequency of BC presentation remains constant at 20-30 per 1000 persons until age 80 (A4). When the BRCA gene is translated into its BRCA protein product, it plays a role in the repairing double DNA breaks such as non-homologous end-joining and homologous recombination DNA repair (A5, A6). It also functions to facilitates cellular responses to DNA damage through blockage of cell proliferation and induction of apoptosis (A7). Thereby, a genetic mutation on BRCA1 and BRCA2 affecting in the functional capability of its protein products would ultimately lead to the susceptibility in mutated-BRCA carriers for BC. | + | The breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) are tumour suppressor genes, and translational protein products expressed in all humans <sup>[39]</sup>. The specific locality of BRCA1 and BRCA2 gene is on chromosome 13 and 17, respectively <sup>[32]</sup><sup>[40]</sup>. Moreover, the significance of such genes is predominantly due to the associated lifetime risk for breast cancer (BC) when mutations are present. This is evidently shown through a prospective cohort study by Kuchenbaecker et al. which revealed the cumulative BC risk to age 80 years to be 72% for BRCA1 and 69% for BRCA2. Additionally, further data has shown a rapid increase in BC incidence from adulthood until ages 30-40 for BRCA1, and until ages 40-50 for BRCA2. However, past the upper-limit for the peak-incidence of each respective gene, the frequency of BC presentation remains constant at 20-30 per 1000 persons until age 80 <sup>[27]</sup>. When the BRCA gene is translated into its BRCA protein product, it plays a role in the repairing double DNA breaks such as non-homologous end-joining and homologous recombination DNA repair <sup>[2]</sup> <sup>[36]</sup>. It also functions to facilitates cellular responses to DNA damage through blockage of cell proliferation and induction of apoptosis <sup>[11]</sup>. Thereby, a genetic mutation on BRCA1 and BRCA2 affecting in the functional capability of its protein products would ultimately lead to the susceptibility in mutated-BRCA carriers for BC. |
| **Evidence that BRCA Involved in DNA Repair** | **Evidence that BRCA Involved in DNA Repair** | ||
| - | There are several studies which evidently validate the evidence of BRCA1 and BRCA2 in DNA repair. Firstly, a study conducted by Foray et al. reveals the inability of irradiated cells to repair DNA double-strand breaks due dysfunctional BRCA1 and BRCA 2 (A8). Secondly, an additional study has demonstrated the impairment of chromosomal-break repair by homologous recombination in BRCA1- and BRCA2-mutant cell-lines. It is further explained in the study that BRCA proteins conjugate with Rad51 recombinase to effectively repair DNA damage, and thus allowing for chromosomal stability (A9, A10). Lastly, Chen et al. reveals the coexistence of BRCA1 and BRCA2 in a biochemical complex which co-localize at the DNA replication sites post-application of hydroxyurea or UV radiation to cause double DNA breaks (A11, A12). | + | There are several studies which evidently validate the evidence of BRCA1 and BRCA2 in DNA repair. Firstly, a study conducted by Foray et al. reveals the inability of irradiated cells to repair DNA double-strand breaks due dysfunctional BRCA1 and BRCA 2 <sup>[17]</sup>. Secondly, an additional study has demonstrated the impairment of chromosomal-break repair by homologous recombination in BRCA1- and BRCA2-mutant cell-lines. It is further explained in the study that BRCA proteins conjugate with Rad51 recombinase to effectively repair DNA damage, and thus allowing for chromosomal stability <sup>[33]</sup>. Lastly, Chen et al. reveals the coexistence of BRCA1 and BRCA2 in a biochemical complex which co-localize at the DNA replication sites post-application of hydroxyurea or UV radiation to cause double DNA breaks <sup>[8]</sup><sup>[42]</sup>. |
| **Alterations in the Cell Cycle** | **Alterations in the Cell Cycle** | ||
| - | Apart from the susceptibility of BC due to the inability of mutant-BRCA to repair DNA breakages; there are additional genes, when unregulated, results in cancerous-cell phenotypes of the breast tissue (A 13). These genes are primarily responsible for regulation of the cell cycle which is an important mechanism for normal cell growth, survivability and replication. | + | Apart from the susceptibility of BC due to the inability of mutant-BRCA to repair DNA breakages; there are additional genes, when unregulated, results in cancerous-cell phenotypes of the breast tissue <sup>[1]</sup>. These genes are primarily responsible for regulation of the cell cycle which is an important mechanism for normal cell growth, survivability and replication. |
| - | Therefore, such disruption in cell-cycle regulatory factors can ultimately lead to sustained proliferative signaling, evasion of growth suppressors, replicative immortality, activation of invasion and metastasis, induction of angiogenesis, and resistance to cell death (A14). In breast cancer, the overexpression of cyclin D1 and E, down-regulation of cyclindependent kinase inhibitors, or the activation of tumour suppressor proteins, retinoblastoma and p55 are the known altered-regulatory cell-cycle proteins that result in the development of cell-malignancy (A15). | + | Therefore, such disruption in cell-cycle regulatory factors can ultimately lead to sustained proliferative signaling, evasion of growth suppressors, replicative immortality, activation of invasion and metastasis, induction of angiogenesis, and resistance to cell death <sup>[12]</sup>. In breast cancer, the overexpression of cyclin D1 and E, down-regulation of cyclindependent kinase inhibitors, or the activation of tumour suppressor proteins, retinoblastoma and p55 are the known altered-regulatory cell-cycle proteins that result in the development of cell-malignancy <sup>[28]</sup>. |
| - | **Up/Down-Regulation of Breast Cancer Genes** | + | **Up/Down-Regulation of Breast Cancer Associated Genes** |
| - | Although the mechanism that malignant tumour cells use to migrate, invade and induce angiogenesis is very well studied, the preliminary cell alterations in which genomic modifications are made are not well known. However, a study by Patsialou et al. in 2012, illustrated that most up-regulated gene networks of migratory great tumour cells included those involved in DNA replication and repair, embryonic and tissue development and cellular movement. Likewise, the most down regulated genes included those involved with nervous system development and function and cell death/cell cycle genes (Patsialou et al., 2012). | + | Although the mechanism that malignant tumour cells use to migrate, invade and induce angiogenesis is very well studied, the preliminary cell alterations in which genomic modifications are made are not well known. However, a study by Patsialou et al. in 2012, illustrated that most up-regulated gene networks of migratory great tumour cells included those involved in DNA replication and repair, embryonic and tissue development and cellular movement. Likewise, the most down regulated genes included those involved with nervous system development and function and cell death/cell cycle genes<sup>[35]</sup>. |
| **Metastatic Process of Breast Cancer** | **Metastatic Process of Breast Cancer** | ||
| - | Epithelial-to-mesenchymal transition (EMT) is the start of breast cancer metastasis. Malignant cells which originate from the primary tumour site invade local tissue and then intravasate into the circulatory system or the lymphatic system respectfully, thereby prompting cell cycle arrest and promoting angiogenesis at secondary tumour sites (Scully et al., 2012). Subsequently, polarized epithelial cells go through biochemical changes due to the EMT process which ultimately allows for the gain of mesenchymal phenotype. With the gain in phenotype comes extra migratory and motility features (Martin et al., 2013). | + | Epithelial-to-mesenchymal transition (EMT) is the start of breast cancer metastasis. Malignant cells which originate from the primary tumour site invade local tissue and then intravasate into the circulatory system or the lymphatic system respectfully, thereby prompting cell cycle arrest and promoting angiogenesis at secondary tumour sites<sup>[41]</sup>. Subsequently, polarized epithelial cells go through biochemical changes due to the EMT process which ultimately allows for the gain of mesenchymal phenotype. With the gain in phenotype comes extra migratory and motility features<sup>[30]</sup>. |
| - | To begin invasion, cancer cells need to manipulate cell-to-cell adhesion through the use of cadherins— to cross the ECM (Scully et al., 2012). Under normal conditions E-cadherin maintain cell-cell junctions while N-cadherins, assist with EMT and thus progresses cancer by inducing ECM degrading enzymes such as MMPs (Wendt et al., 2011). EMT is a two-fold mechanism which not only guides invasion and intravasation into the bloodstream, but also up-regulates proteases involved in the degradation of the ECM. Evidence for such was observed in a study that replaced N-cadherin with E-cadherin, which in turn caused inflammation in mammary tissues eventually leading to breast cancer tumour in mice (Kotb et al., 2011) After the malignant cells have passed the mammary tissue to spread— they must adhere to the ECM of peripheral host cells which is induced via integrins. Passing through the extra cellular matrix (ECM) involves integrins (Scully et al., 2012). Integrin are generally found on basic ECM structures such as collagen, fibrinogen and fibronectin to name a few. Integrins are transmembrane receptors that also are associated with up-regulating ECM-degrading enzymes. For example, one study done on mice showed that integrin α5β1 upregulated matrix matelloproteinase-9 (MMP-9) as cells migrated from the tumor (Rolli et al., 2003). MMPs specifically mediate the ECM degradation at the invadopodial front of invasive breast cancer cells (Scully et al., 2012). Studies have also shown that over-expression of epidermal growth factor receptor (EGFR) and its STP (signal transduction pathway) that causes EMT (epithelial to mesenchymal transition), migration and invasion by increasing the amount of MMP made in the malignant cell (Masuda et al., 2006). Another way the ECM is broken down is by using heparanase to target the heparan sulfate proteoglycan, significant for its role in the integrity of the ECM as well cell matrix adhesion and growth factor receptor interactions. An in vitro and in vivo study by Cohen et al. showed that over expression of heparanase in breast cancer cells increased cell replication and infiltration, thus promoting metastasis (Scully et al., 2012). | + | To begin invasion, cancer cells need to manipulate cell-to-cell adhesion through the use of cadherins— to cross the ECM (extra-cellular matrix)<sup>[41]</sup>. Under normal conditions E-cadherin maintains cell-cell junctions while N-cadherins assist with EMT and thus progresses cancer by inducing ECM degrading enzymes such as MMPs<sup>[49]</sup>. EMT is a two-fold mechanism which not only guides invasion and intravasation into the bloodstream, but also up-regulates proteases involved in the degradation of the ECM. Evidence for such was observed in a study that replaced N-cadherin with E-cadherin, which in turn caused inflammation in mammary tissues eventually leading to breast cancer tumour in mice<sup>[26]</sup>. After the malignant cells have passed the mammary tissue to spread— they must adhere to the ECM of peripheral host cells which is induced via integrins. Passing through the extra cellular matrix (ECM) involves integrins<sup>[41]</sup>. Integrin are generally found on basic ECM structures such as collagen, fibrinogen and fibronectin to name a few. Integrins are transmembrane receptors that also are associated with up-regulating ECM-degrading enzymes<sup>[41]</sup>. For example, one study done on mice showed that integrin α5β1 upregulated matrix matelloproteinase-9 (MMP-9) as cells migrated from the tumor<sup>[38]</sup>. MMPs specifically mediate the ECM degradation at the invadopodial front of invasive breast cancer cells<sup>[41]</sup>. Studies have also shown that over-expression of epidermal growth factor receptor (EGFR) and its STP (signal transduction pathway) causes EMT, migration and invasion by increasing the amount of MMP made in the malignant cell<sup>[31]</sup>. Another way the ECM is broken down is by using heparanase to target the heparan sulfate proteoglycan, significant for its role in the integrity of the ECM as well cell matrix adhesion and growth factor receptor interactions<sup>[41]</sup>. An in vitro and in vivo study by Cohen et al. in 2006 showed that over expression of heparanase in breast cancer cells increased cell replication and infiltration, thus promoting metastasis. |
| - | Tumour cells migrate either on their own or coordinately, however coordinate travel requires the presence of intercellular junctions. Single tumour cells have two pathways to migrate, either protease-dependent mesenchymal movement or protease-independent amoeboid movement (Scully et al., 2012). The former pathway has already been covered, as EMT (epithelial-to-mesenchymal transition) which degrades the ECM and uses MMPs to exit and migrate. However, the latter pathway includes round cells which protrude from pores in the matrix via causing structural deformations in the ECM (Yilmaz et al., 2010). The force in the amoeboid movement is generated by actin/myosin muscular contractions and cortical actin through an STP (signal transduction pathway) such as RhoA/Rho kinase (ROCK) (Yilmaz et al., 2010). The motility of cancer cells to peripheral bodily areas also involves increasing diffusion past pre-existing blood vessels and screening against host immune cells (Gupta et al., 2006). Moreover, breast cancer cells also promote vascular endothelial growth factor-C (VEGF-C). VEGF-C increases lymphatic networking allowing for entry into, and dilation of lymphatic vessels for further spread (He at al., 2005). | + | Tumour cells migrate either on their own or coordinately, however coordinate travel requires the presence of intercellular junctions. Single tumour cells have two pathways to migrate, either protease-dependent mesenchymal movement or protease-independent amoeboid movement<sup>[41]</sup>. The former pathway has already been covered, as EMT (epithelial-to-mesenchymal transition) which degrades the ECM and uses MMPs to exit and migrate. However, the latter pathway includes round cells which protrude from pores in the matrix via causing structural deformations in the ECM<sup>[50]</sup>. The force in the amoeboid movement is generated by actin/myosin muscular contractions and cortical actin through a signal transduction pathway (STP) such as RhoA/Rho kinase (ROCK)<sup>[50]</sup>. The motility of cancer cells to peripheral bodily areas also involves increasing diffusion past pre-existing blood vessels and screening against host immune cells<sup>[19]</sup>. Moreover, breast cancer cells also promote vascular endothelial growth factor-C (VEGF-C). An increase in VEGF-C allows for more lymphatic networking permitting entry into, and dilation of lymphatic vessels for further spread<sup>[21]</sup>. |
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| === Surgical Interventions === | === Surgical Interventions === | ||
| - | Surgery depends on the size and location of tumour, and if the cancer has spread to the lymph nodes. Before surgery, neoadjuvant chemotherapy is commonly used to shrink the tumour so it is relatively easier to remove (Fisher et al., 2002). | + | Surgery depends on the size and location of tumour, and if the cancer has spread to the lymph nodes<sup>[16]</sup>. Before surgery, neoadjuvant chemotherapy is commonly used to shrink the tumour so it is relatively easier to remove<sup>[16]</sup>. |
| - | Lumpectomy is one of the surgical interventions that is the least invasive and is also referred to breast-conserving surgery (BCS), and is always followed up by radiation therapy. BCS involves the removal of a tumour that is small without removing the entire breast tissue. The surgeon makes small incision near the abnormal area, and removes the abnormal mass along with a margin of healthy tissue. BCS is very effective at the early stages of breast cancer when the tumours are locally invasive (Fisher et al., 2002) | + | Lumpectomy is one of the surgical interventions that is the least invasive and is also referred to breast-conserving surgery (BCS), and is always followed up by radiation therapy <sup>[16]</sup>. BCS involves the removal of a tumour that is small without removing the entire breast tissue <sup>[16]</sup>. The surgeon makes small incision near the abnormal area, and removes the abnormal mass along with a margin of healthy tissue<sup>[16]</sup>. BCS is very effective at the early stages of breast cancer when the tumours are locally invasive<sup>[16]</sup>. |
| - | {{ :screen_shot_2017-10-02_at_5.20.12_pm.png |}} **Figure 8:** | + | {{ :screen_shot_2017-10-02_at_5.20.12_pm.png |}} **Figure 8:** Illustrates the removal of a small tumour without removing entire breast tissue using lumpectomy. |
| - | + | ||
| - | Mastectomy is another surgical intervention that is used to treat large tumours that have spread to more than one area in the breast. Mastectomy involves the complete removal of the breast tissue, and the removal of the fascia over the pectoralis muscle. After the removal, the surgeon places tubes where removal has occurred, and these tubes function to remove blood and lymph fluid that collect during the healing process (Fisher et al., 2002) | + | |
| - | {{ :screen_shot_2017-10-02_at_5.17.03_pm.png |}} **Figure 9:** | + | |
| + | Mastectomy is another surgical intervention that is used to treat large tumours that have spread to more than one area in the breast<sup>[16]</sup>. Mastectomy involves the complete removal of the breast tissue, and the removal of the fascia over the pectoralis muscle <sup>[16]</sup>. After the removal, the surgeon places tubes where removal has occurred, and these tubes function to remove blood and lymph fluid that collect during the healing process <sup>[16]</sup>. | ||
| + | {{ :screen_shot_2017-10-02_at_5.17.03_pm.png |}} **Figure 9:** Illustrates the complete removal of the breast tissue using mastectomy. | ||
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| === Radiation Therapy === | === Radiation Therapy === | ||
| - | Radiation therapy uses high-energy rays to destroy cancer cells, and prevent cancer cells from recurring after surgery. It is also used to shrink tumour size before surgery. The therapy damages the genetic material of the cancer cells and stops growth. The high-energy rays can also damage the normal cells, however the normal cells have the ability to repair themselves after the radiation therapy is applied. | + | Radiation therapy uses high-energy rays to destroy cancer cells, and prevent cancer cells from recurring after surgery<sup>[34]</sup>. It is also used to shrink tumour size before surgery<sup>[34]</sup>. The therapy damages the genetic material of the cancer cells and stops growth<sup>[34]</sup>. The high-energy rays can also damage the normal cells, however the normal cells have the ability to repair themselves after the radiation therapy is applied<sup>[34]</sup>. |
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| === Chemotherapy === | === Chemotherapy === | ||
| - | Chemotherapy is a treatment that is used to kill rapidly diving cells, and is highly invasive. There are two types of chemotherapy: neoadjuvant and adjuvant therapy. Neoadjuvant therapy is used before surgery, and targets to shrink the large tumour to increase the chance of patient to have a breast-conserving surgery. The patient is treated with high risk of metastasis without delay, and the therapy can also show if the tumour is responding to the treatment, making the removal of the tumour safer. Adjuvant therapy is used after surgery for patients who have no evidence of cancer. The therapy targets to destroy any cancer cells that may be left behind or cells that have metastasized. Taxol chemotherapy is another specific branch of chemotherapy where taxol binds to the tubulin subunits and stabilizes the microtubules against depolymerisation. This results in the cell to remain in metaphase-anaphase stage, and leads to cell apoptosis than cell replication. Chemotherapy is usually offered to treat early stage breast cancer with a high risk of recurrence or locally advanced breast cancer. Chemotherapy can also cause side effects depending on the type of drug used, the dosage, and overall health. Some common side effects include low blood cell count, hair loss, infection, nausea and vomiting, nervous system damage, and loss of appetite. | + | Chemotherapy is a treatment that is used to kill rapidly diving cells, and is highly invasive. There are two types of chemotherapy: neoadjuvant and adjuvant therapy <sup>[34]</sup>. Neoadjuvant therapy is used before surgery, and targets to shrink the large tumour to increase the chance of patient to have a breast-conserving surgery <sup>[34]</sup>. The patient is treated with high risk of metastasis without delay, and the therapy can also show if the tumour is responding to the treatment, making the removal of the tumour safer. Adjuvant therapy is used after surgery for patients who have no evidence of cancer. The therapy targets to destroy any cancer cells that may be left behind or cells that have metastasized<sup>[34]</sup>. Taxol chemotherapy is another specific branch of chemotherapy where taxol binds to the tubulin subunits and stabilizes the microtubules against depolymerisation<sup>[34]</sup>. This results in the cell to remain in metaphase-anaphase stage, and leads to cell apoptosis than cell replication<sup>[34]</sup>. Chemotherapy is usually offered to treat early stage breast cancer with a high risk of recurrence or locally advanced breast cancer<sup>[34]</sup>. Chemotherapy can also cause side effects depending on the type of drug used, the dosage, and overall health<sup>[34]</sup>. Some common side effects include low blood cell count, hair loss, infection, nausea and vomiting, nervous system damage, and loss of appetite<sup>[34]</sup>. |
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| === Hormonal Therapy === | === Hormonal Therapy === | ||
| - | Hormonal therapy is used to treat breast cancer by adding, blocking, or removing hormones. Hormone therapy is used for breast cancer tissue tested for hormone receptor positive, which means that the cancer cells have receptors for estrogen, progesterone, or both. With these receptors present on the cancer cell, the hormones can attach to the receptors, and help these cells to grow (Canadian Cancer Society). | + | Hormonal therapy is used to treat breast cancer by adding, blocking, or removing hormones. Hormone therapy is used for breast cancer tissue tested for hormone receptor positive, which means that the cancer cells have receptors for estrogen, progesterone, or both <sup>[6]</sup>. With these receptors present on the cancer cell, the hormones can attach to the receptors, and help these cells to grow<sup>[6]</sup>. |
| - | The two common therapies to treat hormone receptor-positive breast cancer are anti-estrogen drugs, and aromatase inhibitors. Tamoxifen is most commonly used as anti-estrogen drug, which blocks the estrogen receptors on cancer cells so cancer cells are not able to use estrogen. Aromatase is an enzyme that the body uses to make estrogen in areas of the body other than the ovaries, such as fat tissues and adrenal glands. Aromatase inhibitors block the action of aromatase enzyme, which decreases levels of estrogen in the body. A decrease in estrogen levels is beneficial because very little estrogen can be used by the cancer cells, minimizing growth of the tumour cell. The figure explains the mechanism of action of aromatase inhibitor and tamoxifen. Estrogen binds to the estrogen receptor, and Tamoxifen competes with with estrogen for ER binding, and aromatase inhibitor reduce synthesis of estrogen from their androgenic precursor. | + | |
| + | The two common therapies to treat hormone receptor-positive breast cancer are anti-estrogen drugs, and aromatase inhibitors. Tamoxifen is most commonly used as anti-estrogen drug, which blocks the estrogen receptors on cancer cells so cancer cells are not able to use estrogen<sup>[6]</sup>. Aromatase is an enzyme that the body uses to make estrogen in areas of the body other than the ovaries, such as fat tissues and adrenal glands<sup>[6]</sup>. Aromatase inhibitors block the action of aromatase enzyme, which decreases levels of estrogen in the body<sup>[6]</sup>. A decrease in estrogen levels is beneficial because very little estrogen can be used by the cancer cells, minimizing growth of the tumour cell<sup>[6]</sup>. | ||
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| ===== Future Treatments ===== | ===== Future Treatments ===== | ||
| === Immunotherapy === | === Immunotherapy === | ||
| - | Current research has progressively contributed to the advancement of breast cancer treatment. The investigations have been especial towards engineered-viral therapy to provide additional modalities of treatment associated with enhanced efficacy. Presently, numerous oncolytic viruses for both monotherapy, and combination therapy are undergoing clinical trials to evaluate the safety and efficacy of treatments. One recent study conducted by Hemminki et al. reveals the impact of the oncolytic adenovirus Ad5/3-E2F- delta24-GMSF in inducing oncolysis and initiating a potent anticancer immune response towards solid non-metastatic tumours. The results showed a radiological disease control rate of 83%, and accumulate of immunological cells to tumours in 9/12 patients (A16). However, the monotherapeutic delivery of oncolytic viruses may not serve optimal success for metastatic and advanced stages of cancer. Thereby, oncolytic viruses can be combined with other anticancer remedies to maximized the efficacy of therapeutics in a synergetic manner. A study conducted by Cerullo et al. demonstrates the immunological effects of cyclophosphamide (CP) in combination with oncolytic adenovirus on cancer patients. The results show that CP-adenoviral treatments had higher rates of disease control than that of the virus alone, as well as overall patient-survivability (A17). | + | Current research has progressively contributed to the advancement of breast cancer treatment. The investigations have been especial towards engineered-viral therapy to provide additional modalities of treatment associated with enhanced efficacy. Presently, numerous oncolytic viruses for both monotherapy, and combination therapy are undergoing clinical trials to evaluate the safety and efficacy of treatments. One recent study conducted by Hemminki et al. reveals the impact of the oncolytic adenovirus Ad5/3-E2F- delta24-GMSF in inducing oncolysis and initiating a potent anticancer immune response towards solid non-metastatic tumours. The results showed a radiological disease control rate of 83%, and accumulate of immunological cells to tumours in 9/12 patients <sup>[22]</sup>. However, the monotherapeutic delivery of oncolytic viruses may not serve optimal success for metastatic and advanced stages of cancer. Thereby, oncolytic viruses can be combined with other anticancer remedies to maximized the efficacy of therapeutics in a synergetic manner. A study conducted by Cerullo et al. demonstrates the immunological effects of cyclophosphamide (CP) in combination with oncolytic adenovirus on cancer patients. The results show that CP-adenoviral treatments had higher rates of disease control than that of the virus alone, as well as overall patient-survivability <sup>[7]</sup>. |
| - | Apart from oncolytic therapies, natural killer (NK) cells have also been a significant focus in the field of immunology due to its role in cancer immunosurveillance and potential to eradicate cancer cells. A recent study conducted by Shenouda et al. demonstrates ex-vivo expansion of activated NK-cells in providing highly effective cytotoxicity against breast cancer cell lines (A18). The ability to accumulate personalized activated NK-cells would enable patients to restore or boost NK-cell levels to optimally combat cancerous cells. Ultimately, these findings may offer various modalities of management for more individualized approaches to breast cancer patients, as well as bridging the next step of innovation towards cancer treatment. | + | Apart from oncolytic therapies, natural killer (NK) cells have also been a significant focus in the field of immunology due to its role in cancer immunosurveillance and potential to eradicate cancer cells. A recent study conducted by Shenouda et al. demonstrates ex-vivo expansion of activated NK-cells in providing highly effective cytotoxicity against breast cancer cell lines <sup>[44]</sup>. The ability to accumulate personalized activated NK-cells would enable patients to restore or boost NK-cell levels to optimally combat cancerous cells. Ultimately, these findings may offer various modalities of management for more individualized approaches to breast cancer patients, as well as bridging the next step of innovation towards cancer treatment. |
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