Cell Cycle & Cancer Development III (BIOL 2006SEF) PDF

BIOL 2006SEF CELLS IN HEALTH AND DISEASE TOPIC 3: CELL CYCLE AND CANCER DEVELOPMENT III Heidi Wong [email protected] Outline Breast Cancer Cervical Cancer Alzheimer disease 2 Breast Cancer Breast cancer caused 670 000 deaths globally in 2022. Roughly half of...

BIOL 2006SEF CELLS IN HEALTH AND DISEASE TOPIC 3: CELL CYCLE AND CANCER DEVELOPMENT III Heidi Wong [email protected] Outline Breast Cancer Cervical Cancer Alzheimer disease 2 Breast Cancer Breast cancer caused 670 000 deaths globally in 2022. Roughly half of all breast cancers occur in women with no specific risk factors other than sex and age. Breast cancer was the most common cancer in women in 157 countries out of 185 in 2022. Breast cancer occurs in every country in the world. Approximately 0.5–1% of breast cancers occur in men. 3  Breast cancer was the commonest cancer among females in Hong Kong. 28.5% of all new cancers in females diagnosed in Hong Kong in 2021 rarely occurred in males. In 2021, 5565 new cases of female breast cancer were diagnosed. The crude incidence rate of female breast cancer was 138.1 per 100 000 female population. The age-standardised incidence rate of female breast cancer was 79.6 per 100 000 standard population. 4  Almost all breast malignancies are adenocarcinomas (>95%). In the most clinically useful classification system, breast cancers are divided based on the expression of hormone receptors—estrogen receptor (ER) and progesterone receptor (PR)—and the expression of the human epidermal growth factor receptor 2 (HER2, also known as ERBB2), into three major groups: 1. ER positive (HER2 negative; 50%–65% of cancers) 2. HER2 positive (ER positive or negative; 10%–20% of cancers) 3. Triple negative (ER, PR, and HER2 negative; 10%–20% of cancers) 5 Epidemiology and Risk Factors Age and Gender Breast cancer is rare in women younger than age 25, but increases in incidence rapidly after age 30 75% of women with breast cancer are older than 50 years of age, and only 5% are younger than 40. The incidence in men is only 1% of that in women. Family History of Breast Cancer approximately 5% to 10% of breast cancers occur in persons who inherit highly penetrant germline mutations in tumor suppressor genes For these individuals, the lifetime risk of breast cancer may be greater than 90%. 6 Geographic Factors The risk is significantly higher in the Americas and Europe than in Asia and Africa. the incidence and mortality rates are five times higher in the United States than in Japan. Some risk factors must be modifiable because migrants from low incidence to high-incidence areas tend to acquire the rates of their new home countries. Diet, reproductive patterns, and breastfeeding practices are thought to be involved. In line with this, breast cancer rates appear to be rising in parts of the world that are adopting Western habits. Race/Ethnicity The highest rate of breast cancer is in women of European descent, largely because of a higher incidence of ER-positive cancers. Hispanic and African American women tend to develop cancer at a younger age and are more likely to develop aggressive tumors. Such disparities are thought to result from a combination of differences in genetics, social factors, and access to health care and are an area of intense study 7 Reproductive History Early age of menarche, nulliparity, absence of breastfeeding, and older age at first pregnancy are all associated with increased risk, probably because each increases the exposure of “at- risk” breast epithelial cells to estrogenic stimulation. Ionizing Radiation Radiation to the chest increases the risk of breast cancer if exposure occurs while the breast is still developing. For example, breast cancer develops in 25% to 30% of women who underwent irradiation for Hodgkin lymphoma in their teens and 20s, but the risk for women treated later in life is not elevated. 8 Other Risk Factors Postmenopausal obesity, postmenopausal hormone replacement, mammographic density, and alcohol consumption also have been implicated as risk factors. The risk associated with obesity probably is due to exposure of the breast to estrogen produced by adipose tissue. In keeping with this, obesity is only associated with an increased risk of tumors that express ER. 9 Abnormalities of Breast Development 1. Accessory breast and nipples Embryologically, the breasts develop from columns of cells called mammary ridges, which extend along the anterior body wall from the armpits to the upper thighs. Most of the ridges disappear in the course of prenatal development However, some people may develop extra breasts or nipples. Extra nipples and breast tissue may be a source of embarrassment to the individual, but usually they do not cause other problems. 10 2. Unequal development of the breasts The fully developed breasts are usually similar in size and shape but are not identical. Occasionally, one breast may fail to develop as much as its counterpart and may be significantly smaller than the opposite breast. 3. Breast Hypertrophy At puberty, one or commonly both female breasts may over respond to hormonal stimulation and enlarge excessively. True breast hypertrophy is primarily caused by overgrowth of fibrous tissue, not glandular tissue or fat. The person may experience considerable back and shoulder discomfort caused by the excessive weight of the breasts. If symptoms are severe, the excessive breast tissue may be surgically resected, after which the breasts may be reconstructed so that they have a more normal size and shape. 11 4. Gynecomastia At puberty, the ductal and fibrous tissue of the adolescent male breast begin to proliferate, forming a distinct nodule of breast tissue under the nipple. This condition, which is called gynecomastia (gyne = woman + mastos = breast), may affect one or both breasts. It appears to result from a temporary physiological imbalance of male and female hormones that sometimes occurs in the male at puberty. Normally, the male secretes both male and female hormones, but male hormones predominate and “cancel out” the effects of the female hormones. Gynecomastia results when there is a temporary increase in estrogen relative to male hormones. The condition is not serious but may cause considerable emotional distress to the affected youth. Nonphysiological gynecomastia may occur in males who use certain drugs, have liver or kidney failure, and may be the result of hormone-producing tumors of the testes. Unilateral breast masses or enlargement in males must be examined to rule out cancer. 12 5. Inflammatory lesions of the breast Acute mastitis is an inflammatory response to a bacterial infection, most often with Staphylococcus aureus. Damage to the nipple during breast feeding allowing penetration of bacteria into the breast tissue is a common cause. The condition is treatable with antibiotics. Subareolar abscesses may become chronic and are associated with manipulations of the nipple area such as piercing and also with cigarette smoking. In severe cases fistulas may form, necessitating a surgical repair. 13 6. Nonproliferative fibrocystic change in the breast Nonproliferative (benign) cystic changes in breast tissue, often called benign cystic disease or benign fibrocystic change (FCC), is a common condition that bears no increased risk for development of cancer. FCC occurs in about one-third of women from the age of 20 to the menopausal period, after which the condition recedes. It is characterized by focal areas of proliferation of glandular and fibrous tissue in the breast associated with localized dilatation of ducts, resulting in the formation of various-sized cysts within the breast. Cystic change appears to be caused by irregularities in the response of the breast tissue to the normal cyclic variations of each menstrual cycle. Clinically, a breast cyst may feel very firm and may appear to be a solid tumor. Ultrasound examination of the breast is often helpful in distinguishing a cystic from a solid mass in the breast. 14 7. Fibroadenoma Fibroadenoma is the most common benign tumor of the female breast. It occurs most frequently in the third and fourth decades but also may present in a juvenile (adolescent) form. The tumors have both an epithelial (glandular) and surrounding stromal component. They are painless, well circumscribed, and slow growing but may increase in size during pregnancy. Tumors are usually solitary and often are detected during routine mammography. 15 Breast Anatomy 16 Classification of Breast Carcinoma Breast cancers are classified according to the site of origin, the presence or absence of invasion, the degree of differentiation, and more recently the molecular characteristics (nature of genes expressed) of the tumor cells. More than 90 percent of carcinomas arise from the epithelium of the ducts and are called ductal carcinomas. The rest arise from the lobules and are designated lobular carcinomas. Ductal carcinoma in situ (DCIS) is the precursor lesion of Ductal carcinoma, while Lobular carcinoma in situ (LCIS) is the precursor lesion of Lobular carcinoma. The therapy and prognosis for invasive breast carcinoma depend on many variables, but current practice focuses in part on the molecular characteristics of the carcinoma cells, which differ from case to case. The characteristics examined include the presence of several cell surface receptors including estrogen receptors (ER) and progesterone receptors (PR), which are almost always present or absent together, and the human epidermal growth factor receptor 2 (HER-2). 17  ER positivity is a favorable prognostic indicator and suggests that the cancer cells may still respond to hormonal stimulation. Patients with these cancers are excellent candidates for drugs that block the effects of estrogens (such as tamoxifen) and slow the growth of the cancer cells. Some breast carcinomas overexpress (make excessive amounts of) the HER-2 protein and other genes associated with HER-2. These carcinomas are aggressive and have a poor prognosis. However, they are candidates for therapy using antibodies that target the HER-2 receptor (the monoclonal antibody trastuzumab and others) or for a drug that blocks the pathway stimulated by HER-2 ((lapatinib, a tyrosine kinase inhibitor). 18  Luminal A carcinomas make up about 50 percent of cases and are most like the normal (non-neoplastic) breast epithelial cells. Luminal A cancers are low grade; that is, they are most similar to the normal cells they originate from and are generally ER positive. Individuals with these carcinomas have an excellent prognosis and are treated with hormonal therapy. Luminal B tumors (15 percent to 20 percent of cases) have a higher grade than Luminal A tumors but usually still express some level of ER. Individuals with these carcinomas have a poorer prognosis and are treated with both hormonal and other forms of chemotherapy. 19  Individuals with basal-like tumors (15 percent to 20 percent of cases) have a poor prognosis. Their pattern of gene expression is most similar to the myoepithelial cells that line breast Terminal Duct Lobular Units (TLDUs). These tumors are commonly of the triple-negative type, lacking in ER, PR, and HER-2. Most tumors in BRCA1-positive individuals are of this type. Although the tumors are sensitive to chemotherapy, patients have a high relapse rate, and the tumors tend to metastasize to the viscera and brain. HER-2-positive tumors (10% of cases) are extremely aggressive. These tumors contain multiple copies of the gene responsible for the HER-2 protein and have large amounts of the HER-2 receptor on their surface. 20 Pathogenesis Germ line mutations in two genes, BRCA1 and BRCA2, account for 50% of cases of familial breast cancer. In addition to breast cancer, women with BRCA1 mutations have a substantially higher risk for developing epithelial ovarian cancers, and men have a slightly higher risk for developing prostate cancer. Likewise, germ line mutations in the BRCA2 gene increase the risk for developing breast cancer in both men and women, as well as cancers originating from the ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B lymphocytes. Although the functions of BRCA1 and BRCA2 have not been elucidated fully, cells with a defective version of these genes develop chromosomal breaks and severe aneuploidy. BRCA1 and BRCA2 are classic tumor suppressor genes, in that cancer arises only when both alleles are inactivated or defective BRCA1 and BRCA2 encode proteins that are required for repair of certain kinds of DNA damage. 21 22 Major pathways of breast cancer development 1. ER-positive cancers. Morphologically recognized precursor lesions include flat epithelial atypia, ADH, and DCIS, all of which share certain genomic events with invasive ER-positive carcinomas, such gains of chromosome 1, losses of chromosome 16, and mutations of PIK3CA (the gene encoding PI3K). By gene expression profiling, these cancers are classified as “luminal.” This is the type of cancer that arises most commonly in individuals with germline BRCA2 mutations. 2. overexpressed HER2 because of gene amplification These cancers may be positive or negative for ER and are usually associated with germline TP53 mutations. 3. Basal-like tumor A possible precursor lesion is atypical apocrine adenosis, which shares features with apocrine DCIS. The least common but molecularly most distinctive type of breast cancer is negative for ER and HER2 These cancers have loss of BRCA1 and TP53 function and are genomically unstable. The majority of triple-negative cancers are classified as “basal-like” by gene expression profiling. 23 Diagnosis 1. Clinical Breast Exam: A healthcare professional manually checks for lumps or other changes. 2. Imaging Tests:  Mammogram: An X-ray of the breast to detect abnormalities.  Ultrasound: Uses sound waves to differentiate between solid masses and fluid-filled cysts.  MRI: Offers detailed images, especially useful for high-risk patients or complex cases. 3. Biopsy: If an abnormality is found, a sample of tissue is taken to examine under a microscope.  Core Needle Biopsy: Uses a larger needle to remove a small cylinder of tissue.  Surgical Biopsy: Removing a part or all of a lump for examination. 4. Cytology  Fine-Needle Aspiration: Uses a thin needle to extract cells or fluid. 4. Additional Tests:  Hormone Receptor Tests: Determines if cancer cells have estrogen or progesterone receptors.  HER2 Test: Checks for overexpression of the HER2 protein, which can influence treatment options. 24  Treatment 1. Surgery:  Lumpectomy: Removal of the tumor and a small margin of surrounding tissue.  Mastectomy: Removal of one or both breasts, partially or completely.  Sentinel Lymph Node Biopsy: Checks if cancer has spread to lymph nodes.  Axillary Lymph Node Dissection: Removal of additional lymph nodes if cancer is found. 2. Radiation Therapy:  Uses high-energy rays to target and kill cancer cells, often following surgery to eliminate remaining cancer cells. 3. Chemotherapy:  Uses drugs to destroy cancer cells, either before surgery (neoadjuvant) to shrink tumors or after (adjuvant) to kill remaining cells. 4. Hormonal (Endocrine) Therapy:  For hormone receptor-positive breast cancers, therapies like tamoxifen or aromatase inhibitors block hormones that fuel cancer growth. 5. Targeted Therapy:  Drugs that target specific characteristics of cancer cells, such as HER2-positive cancers (e.g., trastuzumab). 6. Immunotherapy:  Uses the body's immune system to fight cancer, effective in some cases of breast cancer. 7. Bone-Directed Therapy:  For cancers that have spread to the bone, treatments like bisphosphonates or denosumab help protect bone health. 25  Prevention 1.Maintain a Healthy Weight: Being overweight or obese is a risk factor for breast cancer, especially after menopause. Maintaining a healthy weight through a balanced diet and regular exercise can help reduce this risk. 2. Regular Physical Activity: Engaging in regular physical activity, such as brisk walking, running, or other forms of exercise, can help lower the risk of breast cancer. Aim for at least 150 minutes of moderate-intensity exercise per week. 3. Healthy Diet: Eat a diet rich in fruits, vegetables, whole grains, and lean proteins. Limit the consumption of processed foods, red meat, and sugary beverages. A healthy diet can help reduce the risk of cancer. 4. Limit Alcohol Consumption: Alcohol consumption is linked to an increased risk of breast cancer. Limiting alcohol intake to no more than one drink per day for women can help lower this risk. 26 5. Avoid Smoking: Smoking is associated with a higher risk of breast cancer, particularly in premenopausal women. Quitting smoking can reduce this risk and improve overall health. 6. Breastfeeding: Breastfeeding can reduce the risk of breast cancer, especially if done for an extended period. If possible, aim to breastfeed your baby for at least several months. 7. Hormone Replacement Therapy (HRT): Discuss the risks and benefits of hormone replacement therapy with your healthcare provider if you are considering it for menopausal symptoms. Long-term use of combined estrogen and progestin HRT may increase the risk of breast cancer. 8. Screening and Early Detection: Regular mammograms and clinical breast exams can help detect breast cancer at an early stage when treatment is most effective. Follow your healthcare provider's recommendations for screening. 9. Genetic Testing and Counseling: If you have a family history of breast cancer or other risk factors, consider genetic testing and counseling to assess your risk and explore preventive options. 27 Cervical Cancer Cervical cancer is the fourth most common cancer in women globally with around 660 000 new cases and around 350 000 deaths in 2022. The highest rates of cervical cancer incidence and mortality are in low- and middle-income countries. This reflects major inequities driven by lack of access to national HPV vaccination, cervical screening and treatment services and social and economic determinants. Cervical cancer is caused by persistent infection with the human papillomavirus (HPV). Women living with HIV are 6 times more likely to develop cervical cancer compared to women without HIV. Prophylactic vaccination against HPV and screening and treatment of pre-cancer lesions are effective strategies to prevent cervical cancer and are very cost-effective. Cervical cancer can be cured if diagnosed at an early stage and treated promptly. Countries around the world are working to accelerate the elimination of cervical cancer in the coming decades, with an agreed set of three targets to be met by 2030. 28  Cervical cancer was the seventh commonest cancer among females in Hong Kong and accounted for 3.1% of all new cancer cases in females in 2021. In 2021, 596 new cases of cervical cancer were diagnosed. The crude incidence rate of cervical cancer was 14.8 per 100 000 female population. The age-standardised incidence rate* of cervical cancer was 8.9 per 100 000 standard population. 29 Causes HPV is a common sexually transmitted infection which can affect the skin, genital area and throat. Almost all sexually active people will be infected at some point in their lives, usually without symptoms. In most cases the immune system clears HPV from the body. Persistent infection with high-risk HPV can cause abnormal cells to develop, which go on to become cancer. Persistent HPV infection of the cervix (the lower part of the uterus or womb, which opens into the vagina – also called the birth canal) if left untreated, causes 95% of cervical cancers. Typically, it takes 15–20 years for abnormal cells to become cancer, but in women with weakened immune systems, such as untreated HIV, this process can be faster and take 5–10 years. Risk factors for cancer progression include the grade of oncogenicity of the HPV type, immune status, the presence of other sexually transmitted infections, number of births, young age at first pregnancy, hormonal contraceptive use, and smoking. 30  Nearly all cervical cancers are caused by persistent infection by high-risk Human Papillomavirus (hr-HPV) which are primarily transmitted through sexual contact. Most people who are infected by hr-HPV do not have symptoms and the infections will clear up on their own. However, persistent infection by hr-HPV can cause abnormal cervical cell changes (precancerous changes), which may subsequently progress to cancer. High-risk HPV genotypes cause the vast majority (>90-95%) of squamous cell carcinomas 12 HPV types are classified by WHO as oncogenic: 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59 Two types (16 and 18) are responsible for 70% of all squamous cell carcinomas 31 Primary Prevention - Prophylactic Vaccination Three vaccines currently available:  the bivalent (Cervarix) against HPV 16/18,  the quadrivalent (Gardasil) against HPV 6/11/16/18  the nonavalent (Gardasil 9) against HPV 6/11/16/18/31/33/45/52/58 All of them offer protection against HPV types 16 and 18 (the two most common strains in cervical cancer) which account for about 70% of cervical cancer. 32  For girls and women aged 9 or above who have not started sexual activities, HPV vaccine can significantly reduce the chance of getting cervical cancer. For women who have been sexually active, the effectiveness of HPV vaccine varies. They should discuss with their doctor first before deciding on having vaccination. Vaccination is not 100% effective in preventing cervical cancer. No matter they have been vaccinated or not, all sexually active women should have regular cervical screening. 33 Secondary Prevention- Cervical Screening Target population: all women from age 25 or the time of commencing sexual activity (whichever is later) until the age of 64. women over 65 years who have never had cervical cytology and have a history of being sexually active, should be screened. Screening Interval (Cytology): Screening at 3-yearly intervals, after 2 consecutive normal annual cytology tests, is recommended. Chronically immunosuppressed women will need annual screening. *Refer to The Hong Kong College of Obstetricians and Gynaecologists (HKCOG) guideline on Cervical Cancer Prevention and Screening in 2016 34 Risk factors Early age at first intercourse Multiple sexual partners Male partner with multiple previous sexual partners Persistent infection by high-risk strains of papillomavirus 35  Human Papillomavirus (HPV) Papillomaviruses are a large group of non-enveloped double-stranded DNA viruses that belong to the papillomavirus genus of the Papillomaviridae family. HPV can infect epithelial cells of the skin as well as oral and genital mucosa. HPV spreads through intimate skin-to-skin contact, including vaginal, anal, or oral sex. More than 100 types of HPV have been detected so far, which have been further categorized as cutaneous or mucosal depending on their tissue tropism and as high risk (HR) or low risk (LR) depending on their oncogenic capacity. HPV is currently among the most common sexually transmitted infections worldwide. According to the Centers for Disease Control and Prevention (CDC), around 13 million new cases of HPV are detected each year. In fact, it is estimated that around 80 percent of sexually active men and women get infected with HPV at some point in their lives. (Perez-Campos Mayoral et al., 2018) 36 37  Pathogenesis Oncogenic activities of E6 The E6 protein binds to and mediates the degradation of p53, and also stimulates the expression of TERT, the catalytic subunit of telomerase, which you will recall contributes to the immortalization of cells. E6 from high-risk HPV types has a higher affinity for p53 than E6 from low-risk HPV types, a property that is likely to contribute to oncogenesis. Oncogenic activities of E7 The E7 protein has effects that complement those of E6, all of which are centered on speeding cells through the G1-S cell cycle checkpoint. It binds to the RB protein and displaces the E2F transcription factors that are normally sequestered by RB, promoting progression through the cell cycle. As with E6 proteins and p53, E7 proteins from high-risk HPV types have a higher affinity for RB than do E7 proteins from low-risk HPV types. E7 also inactivates the CDK inhibitors p21 and p27, and binds and presumably activates cyclins E and A. 38  An additional factor that contributes to the oncogenic potential of HPVs is viral integration into the host genome. In benign warts, the HPV genome is maintained in a nonintegrated episomal form, while in cancers, the HPV genome is randomly integrated into the host genome. Integration interrupts a negative regulatory region in the viral DNA, resulting in overexpression of the E6 and E7 oncoproteins. Furthermore, cells in which the viral genome has integrated show significantly more genomic instability, which may contribute to acquisition of pro-oncogenic mutations in host cancer genes. 39 Possible consequences of HPV infection 40  HPV variants are classified as high-risk or low-risk types based on their propensity to induce carcinogenesis. High-risk HPV infection is the most important risk factor for the development of SIL that can progress to carcinoma. Two high-risk HPV viruses, types 16 and 18, account for approximately 70% of cases of SIL and cervical carcinoma. In general, infections with high-risk HPV types are more likely to persist, which is a risk factor for progression to carcinoma. These HPV types also show a propensity to integrate into the host cell genome, an event that is linked to progression. Low-risk HPV variants (e.g., types 6 and 11) associated with the development of condylomas of the lower genital tract 41 Spectrum of squamous intraepithelial lesions (SIL) 42 43 Diagnosis 1. Pap Smear (Pap Test):  Screens for precancerous or cancerous cells on the cervix. 2. HPV Testing:  Checks for the presence of high-risk human papillomavirus types that can lead to cervical cancer. 3. Colposcopy:  An examination of the cervix using a special magnifying instrument to identify abnormal areas. 4. Biopsy:  Punch Biopsy: Removes small samples of cervical tissue.  Endocervical Curettage: Scrapes cells from the cervical canal.  Cone Biopsy (Conization): Removes a larger, cone-shaped section of tissue. 5. Imaging Tests:  CT Scan, MRI, or PET Scan: Used to determine the extent of cancer spread. 44 Treatment 1. Surgery:  Conization: Removes a cone-shaped section of abnormal tissue.  Hysterectomy: Removal of the uterus, can be simple or radical.  Trachelectomy: Removal of the cervix, preserving fertility.  Pelvic Exenteration: Extensive surgery for advanced cancer. 2. Radiation Therapy:  Often used in combination with chemotherapy to destroy cancer cells. 3. Chemotherapy:  Uses drugs to kill or slow the growth of cancer cells, often used with radiation. 4. Targeted Therapy:  Drugs like bevacizumab target specific pathways that cancer cells use to grow. 5. Immunotherapy:  Helps the immune system recognize and attack cancer cells, effective in some cases. 45 Prevention 1. HPV Vaccination: The human papillomavirus (HPV) vaccine protects against the high-risk HPV types that cause most cervical cancers. Vaccination is most effective when given before becoming sexually active. 2. Regular Pap Smears and HPV Testing: Regular cervical cancer screening with Pap smears and HPV testing can detect precancerous changes or HPV infections early, allowing for prompt treatment before cancer develops. 3. Safe Sex Practices: Practicing safe sex, including using condoms, can reduce the risk of HPV infection, which is a major risk factor for cervical cancer. 4. Limiting Sexual Partners: Having multiple sexual partners increases the risk of HPV infection and cervical cancer. Limiting the number of sexual partners can help reduce this risk. 5. Avoiding Smoking: Smoking is associated with an increased risk of cervical cancer. Quitting smoking can help lower this risk. 46 6. Maintain a Healthy Diet: Eating a balanced diet rich in fruits, vegetables, whole grains, and lean proteins can support overall health and reduce the risk of cervical cancer. 7. Maintain a Healthy Weight: Being overweight or obese is a risk factor for several types of cancer, including cervical cancer. Maintaining a healthy weight through diet and exercise can help lower this risk. 8. Regular Exercise: Engaging in regular physical activity has been linked to a reduced risk of various cancers, including cervical cancer. Aim for at least 150 minutes of moderate-intensity exercise per week. 9. Avoiding Hormonal Contraceptives: Long-term use of certain hormonal contraceptives may slightly increase the risk of cervical cancer. Discuss your contraceptive options with your healthcare provider. 47 Alzheimer’s Disease Alzheimer disease (AD) is the most common cause of dementia in older adults, with an increasing incidence as a function of age. The incidence is about 3% in individuals 65 to 74 years of age, 19% in those 75 to 84 years of age, and 47% in those older than 84 years of age. Most cases of AD are sporadic, but at least 5% to 10% are familial. Sporadic cases rarely present before 50 years of age, but early onset is seen with some heritable forms. The disease usually manifests with the insidious onset of impaired higher intellectual function, memory impairment, and altered mood and behavior. Over time, disorientation and aphasia, findings indicative of severe cortical dysfunction, often develop; those in the final phases of AD are profoundly disabled, often mute and immobile. Death usually occurs from intercurrent pneumonia or other infections. 48 Pathogenesis The brain has billions neurons, each with an axon and many dendrites. To stay healthy, neurons must communicate with each other, carry out metabolism and repair themselves. There are wo signature lesions in AD: 1. Neuritic plaques/ β-amyloid plaques, which are dense deposits of protein and cellular material that accumulate outside and around nerve cells 2. Neurofibrillary tangles, which are twisted fibers that build up inside the nerve cell 49 1. Neuritic plaques Deposits of a protein fragment called β–amyloid (Aβ), that accumulates in the spaces between the nerve cells (neurons). Amyloid precursor protein (APP) is the precursor of amyloid plaque APP sticks through the neuron membrane Enzymes like β-secretase and α-secretase cut the APP into fragments of protein, including Aβ Aβ fragments come together in clumps to form plaques In AD, many of these clumps form, disrupting the work of neurons. This affects the hippocampus and other areas of the cerebral cortex. 50 2. Neurofibrillary tangles Neurons have an internal support structure partly made up of microtubules A protein called “tau” helps to stabilize microtubules In AD, “tau” changes, causing microtubules to collapse and “tau” proteins clump together to form neurofibrillary tangles 51  The fundamental abnormality in AD is the accumulation of two proteins (β-amyloid and tau) in specific brain regions, in the forms of plaques and tangles, respectively these changes result in secondary effects including neuronal dysfunction, neuronal death, and inflammatory reactions. Plaques are deposits of aggregated β-amyloid peptides in the neuropil, while tangles are aggregates of the microtubule binding protein tau, which develop intracellularly and then persist extracellularly after neuronal death. Both plaques and tangles appear to contribute to neural dysfunction. 52 Aβ peptide genesis and consequences in Alzheimer disease 53  The pathogenesis of AD involves Aβ and Tau deposits Aβ is created when the transmembrane protein amyloid precursor protein (APP) is sequentially cleaved by the enzymes β-amyloid–converting enzyme (BACE) and γ-secretase. APP also can be cleaved by α-secretase and γ-secretase, liberating a different peptide that is nonpathogenic. Because neurofibrillary tangles contain the tau protein, there has been much interest in the role of this protein in AD. Tau is a microtubule-associated protein present in axons in association with the microtubular network. With the development of tangles in AD, tau shifts to a somatic-dendritic distribution, becomes hyperphosphorylated, and loses the ability to bind to microtubules. The formation of tangles is an important component of AD, but the mechanism of tangle injury to neurons remains poorly understood. 54 Diagnosis 1. Medical History:  Review of symptoms, family history, and medical conditions. 2. Cognitive and Neuropsychological Tests:  Assess memory, problem-solving, attention, and language skills. 3. Physical and Neurological Exams:  Evaluate overall health and check for signs of neurological issues. 4. Laboratory Tests:  Blood tests to rule out other causes of symptoms. 5. Brain Imaging:  MRI or CT Scan: Detects brain changes, such as atrophy or other abnormalities. 6. Cerebrospinal Fluid Analysis:  Tests for biomarkers associated with Alzheimer's. 7. Genetic Testing:  In certain cases, tests for genetic markers linked to Alzheimer's risk. 55 Treatment 1. Medications:  Cholinesterase Inhibitors: Donepezil, rivastigmine, and galantamine help with memory and thinking.  Memantine: Regulates glutamate activity to improve cognition and daily functioning. 2. Lifestyle and Supportive Therapies:  Cognitive Stimulation: Engaging activities to boost mental function.  Exercise: Regular physical activity to improve mood and health.  Diet: Balanced nutrition, like the Mediterranean diet, supports brain health. 3. Behavioral Strategies:  Establishing routines and using reminders to help with daily tasks.  Managing behavioral changes with therapy and support. 4. Support for Caregivers:  Education, resources, and support groups to assist those caring for individuals with Alzheimer's. 56 Prevention 1. Regular Physical Exercise: Engaging in regular physical activity can help improve blood flow to the brain, reduce the risk of cardiovascular diseases, and promote overall brain health. 2. Healthy Diet: Following a balanced diet rich in fruits, vegetables, whole grains, lean proteins, and healthy fats can provide essential nutrients for brain health. Consider a Mediterranean diet, which has been associated with a lower risk of Alzheimer's disease. 3. Mental Stimulation: Keeping the brain active through activities such as reading, puzzles, learning new skills, and social interactions can help maintain cognitive function and reduce the risk of cognitive decline. 4. Quality Sleep: Prioritize getting enough high-quality sleep, as sleep plays a crucial role in memory consolidation and overall brain health. 5. Manage Chronic Conditions: Keeping conditions like diabetes, hypertension, and high cholesterol under control through proper management and treatment can help reduce the risk of Alzheimer's disease. 57 6. Social Engagement: Maintaining social connections and being actively involved in social activities can help promote brain health and reduce the risk of cognitive decline. 7. Stress Management: Chronic stress can have negative effects on brain health, so practicing stress-reducing techniques such as mindfulness, meditation, yoga, or deep breathing exercises can be beneficial. 8. Heart-Healthy Habits: What is good for the heart is often good for the brain. Maintaining a healthy weight, not smoking, and controlling cholesterol levels can help reduce the risk of Alzheimer's disease. 9. Regular Health Check-ups: Regular visits to healthcare providers for preventive screenings and check-ups can help detect and manage any potential risk factors for Alzheimer's disease early on. 10. Stay Mentally Active: Engage in activities that challenge your brain, such as learning new skills, playing musical instruments, or solving puzzles, to keep your brain active and healthy. 58 Reference Vinay Kumar, Abul K. Abbas, Jon C. Aster, Andrea T. Deyrup. (2022). Robbins & Kumar Basic Pathology (11th ed.). Elsevier. 59 Concept Check (T or F) 1. Breast cancer is always hereditary. 2. Breast cancer only affects women. 3. Gynecomastia results when there is a temporary increase in progesterone relative to male hormones. 4. Fibroadenoma is the most common malignant tumor of the female breast. 5. Breast cancer can be begun in the milk-producing ducts of the breast. 6. Mutations in the BRCA1 and BRCA2 genes are associated with an increased risk of developing breast cancer. 7. HER2-positive breast cancer is a subtype of breast cancer that tends to be more aggressive. 8. The presence of estrogen and progesterone receptors in breast cancer cells can help guide treatment decisions. 9. Mammograms are the only way to detect breast cancer. 10. Hormone replacement therapy (HRT) can increase the risk of developing breast cancer. 60 11. Cervical cancer is hereditary. 12. Human papillomavirus (HPV) is the primary cause of cervical cancer. 13. Cervical cancer is the only gynecologic cancer that can be prevented with a vaccine. 14. Cervical cancer can be detected through a blood test. 15. Cervical Screening at 3-yearly intervals, after 2 consecutive normal annual cytology tests, is recommended. 16. Low-grade squamous intraepithelial lesions (LSIL) are more likely to progress to invasive cervical cancer compared to high-grade squamous intraepithelial lesions (HSIL). 17. LSIL may regress or resolve on its own without treatment. 18. HPV E6 and E7 oncogenes play a critical role in the development of cervical cancer by inactivating tumor suppressor proteins. 19. It takes 15–20 years for abnormal cells to become cervical cancer. 20. HPV types 16 and 18 are the two most common strains in cervical cancer which account for 100% cervical cancer. 61 21. Alzheimer disease (AD) is the most common cause of dementia in young adults. 22. Tau protein normally plays a role in maintaining the structure of neurons. 23. In Alzheimer disease, there is a buildup of abnormal protein deposits in specific brain regions. 24. Tau is a microtubule-associated protein present in axons. 25. Regular physical exercise is not associated with a reduced risk of developing Alzheimer disease. 62