Case 7 Flashcards
What are the treatments used to treat breast cancer?
- tamoxifen
- herceptin
- breast conserving surgery
- mastectomy
- axillary node clearance
- radiotherapy
- chemotherapy
- oophorectomy
What is Tamoxifen? and how does it work?
Tamoxifen (ER)
- Selective oestrogen receptor modulators, or SERMs, selectively stimulate or inhibit the oestrogen receptors
- Tamoxifen is a SERM
- It blocks the action of oestrogen (an antagonist) in breast tissue by binding to the oestrogen receptors, thereby preventing oestrogen molecules from binding to it
- This means there is no change in shape of the receptor – therefore coactivators cannot bind to it, thus no transcription
- Anti-oestrogen drug
- If remove oestrogen from the blood stream, the growth factor stimulus is stopped, then the cancer cells will stop growing and then they apoptose and die
- Tamoxifen is a hormone therapy drug used to treat ER+ breast cancer in pre-menopausal and post-menopausal women and in men
What is Herceptin? and what does it do?
- Herceptin is a monoclonal antibody that binds to HER2
- This prevents dimerization, thus preventing the activation of pathways leading to cell proliferation and cell survival
- It is a form of targeted therapy
- It is also used as an adjuvant therapy, after surgery
- Herceptin – monoclonal antibody that links onto another growth receptor called HER2 – block receptor means breast cancer will stop growing and apoptose – 1 in 5 of breast cancers have over expression of this growth factor
What breast conserving surgery?
Breast conserving surgery (lumpectomy) (wide local excision)
- Removal of a breast lump, together with some surrounding tissue
- Followed by radiotherapy treatment to the remaining breast tissue
- The operation removes the least amount of breast tissue, but leaves a small scar and sometimes a small dent in the breast
What is a mastectomy?
- Removal of entire breast tissue because of the size of the tumour
- Radical mastectomy: removal of entire breast tissue, pectoralis major and minor and lymph nodes
- Modified radical mastectomy: removal of entire breast tissue, pectoralis minor and lymph nodes, but not pectoralis major
What is axillary node clearance?
Removal of some (sentinel node) or all of the lymph nodes in the axilla to check for malignancy
What is radiotherapy treatment? when is it given? how does it work?
- Given to the conserved breast after wide local excision to reduce local recurrence and to the chest wall after mastectomy
- The ionising radiation damages the DNA of the exposed tissue, leading to cell death – to avoid healthy cells being affected, shaped radiation beams are aimed from several angles of exposure providing a larger absorbed dose there than in the surrounding, healthy tissue
What is chemotherapy? what is the aim? when is it used?
- Use of anti-cancer (cytotoxic) drugs to destroy malignant cells
- The aim of chemotherapy is to do the maximum damage to cancer cells while causing the minimum damage to healthy tissue
- Chemotherapy is often administered as adjuvant treatment, following surgery
What is oophorectomy? why is this performed?
- Surgical procedure for the removal of an ovary or ovaries
- This is often performed due to diseases such as cancer; as prophylaxis to reduce the chances of developing ovarian cancer or breast cancer
- Women who are high-risk BRCA mutation carriers are at a substantially higher risk of developing breast cancer or ovarian cancer
What is often given after surgery and radiotherapy?
- Adjuvant (applied after initial treatment for cancer, especially to suppress secondary tumour formation) therapy – after surgery and radiotherapy
- Adjuvant drugs in case – even if nothing in scans
- Stop metasteses before they may be picked up on scans – they have to be 2-3 cm in diameter to be picked up – already a lot of malignant cells – quite difficult for chemotherapy to destroy all that
What is a sentinel node biopsy?
- Those profuse lymphatic pathways in the breast tends to go through a single lymph node as a way into the body - sentinel node
- Biopsy has become a standard of care
What are indications for mastectomy? (over wide local incision & radiotherapy)
- Multifocality (more than one lump)
- Local recurrence (you can’t have radiotherapy more than once in a particular part of your body)
- DCIS or invasion >4cm
- BRCA gene mutation
- Roughly a third of women with breast cancer have a mastectomy
What are the options for reconstructive surgery?
- Implant behind skin
- T-Dap – from back
- Tummy – use tissue from here
- Immediate or delayed reconstruction
Describe interphase of the cell cycle.
- G1, S phase (DNA synthesis), G2
- G1 = diploid, G2 = tetraploid
- G0 is a stage that differentiating cells sit in once they’ve exited the cell – most cells are sitting in G0
- For some cells they stay in G0 permanently, for example cardiomyocytes and neurones – can’t re-enter the cell cycle, however things like hepatocytes are very good at re-entering the cell cycle
What controls cell cycle progression?
CONTROL OF CELL CYCLE PROGRESSION (some proteins change concentration during the cell cycle, e.g. Cyclin B
- Cyclin B expression peaks during mitosis (only present during late G2 and mitosis)
- Essential for controlling transition between G2 and mitosis
- Cyclin B associates with cyclin dependent kinase 1 (CDK1) to activate CDK1
- CDK1 adds phosphates to proteins to change the function of those proteins
- Cyclin B/CDK1 phosphorylate proteins to cause mitosis
Phosphorylating these:
- Histone1 – chromosome condensation
- MAP – spindle formation
- Lamin – nuclear envelope breakdown
Different cyclin/CDK partners are required for progression through different steps of the cell cycle
CyclinD / CDK4 – transition from G0 into G1
CyclinE / CDK2 – G1 to S phase
CyclinA / CDK2 – to get through whole of S phase and complete it
CyclinA / CDK1 – G2 to mitosis
CyclinB / CDK1 – G2 to mitosis
What regulates cell growth?
- Reducing myc function decrease cell size
- The more myc you have the faster the cell will grow
- If all the cells are smaller the whole organism will be smaller, even if there are the same number of cells in each organism
- Increasing myc function leads to enlarged cells
What are the different types of cell death?
Necrosis – accidental cell death due to injury which releases cellular contents leading to an inflammatory response
Apoptosis – the organised destruction of a cell which is initiated by either a signal from a neighbouring cell or the cell itself due to sensed internal damage – this process doesn’t cause an inflammatory response and is commonly referred to as programmed cell death – it’s planned – any broken off bits of the cells are phagocytosed and the parts are reused
- Gets rid of damaged cells or unwanted cells (e.g. areas between fingers and toes)
What regulates apoptosis?
Extracellular signals and intracellular signals can induce apoptosis
- Extrinsic – neighbouring cells kills a damaged or infected cell
- e.g. CD8 cell recognising a cell has aa viral infection and killing it – does this through TNFalpha or FAZ-L – cytotoxic T cell will produce the protein, which will bind to its receptor on the cell, which will cause that receptor to trimerise – once receptor is trimerized, it will recruit DISC (death induced signalling complex) – once you’ve assembled DISC, it will activate a set of proteases called caspases – once these are activated, the cell will be destroyed – they chop up proteins inside the cell that stop the cell from working
- Intrinsic – a cell recognises that it is damaged, and it will control the localisation of the protein Bax (normally cytosolic) – it will add to the outer membrane of the mitochondria – there it will make a pore, which means that proteins (e.g. cytochrome C) found in the intramembranous space will escape – once cytochrome C has escaped, it will activate the proteases, caspases, and the cell will die
Describe familial cancers. (percentage of cancers, type of mutation, mutation of what, what else is necessary, susceptibility, syndromic, example)
- 1% of all cancers
- Single gene mutations (Mendelian disorders)
- Most are inherited mutations of tumour suppressor genes
- Further genetic events are necessary – even though the mutated gene is inherited, it isn’t sufficient for malignancy
- The inherited mutated gene increases cancer susceptibility – significant inherited predisposition
- Syndromic – they can have more than one change as part of the condition, not just the cancer
- Example: BRCA1 gene which is a predisposition to breast and ovarian cancer
Describe sporadic cancers. (percentage of cancers, predisposition, result of what, results in what)
- 99% of all cancers
- No significant inherited predisposition
- Result of exposure to carcinogenic agents and unrepaired DNA replication errors
- Results in somatic activation/inactivation of cancer genes – somatic genetic alterations
Compare familial and sporadic cancers.
Familial:
- early onset (already had one mutation)
- > 1 tumour of same type (because all of the cells are carrying first mutation)
- other types of tumours
- tumour cells: both copies of TSG inactivated
- all other cells: one copy of TSG inactivated
Sporadic:
- later onset
- single tumour usually
- no other tumours usually
- tumour cells: both copies of TSG inactivated
- all other cells: normal
What are the general types of cancer?
- Adenoma: benign tumour of the glands
- Carcinoma: malignant tumour of epithelial tissue (more than 90% of all cancers)
- Lymphoma: lymphocytes or lymphatic system
- Sarcoma: malignant tumour of stromal tissue (stromal cells are connective tissue cells of an organ found in the loose connective tissue – these are most often associated with the uterine mucosa and the ovary as well as the haematopoietic system and elsewhere)
- Blastoma: immature/pre-cursor cells (dendrites – white blood cells)
- Papilloma: benign epithelial tumour – may arise from skin, mucous membrane, or glandular ducts – protrude from the surface
What are the differences between benign and malignant tumours?
- Benign tumours
- Capsule surrounds tumour
- Well differentiated cells
- Structure is similar to tissue organ
- Low mitotic activity – slow rate of growth
- No invasion of surrounding tissue
- No metastasis - Malignant tumours
- No capsule
- Lack of differentiation (anaplasia)
- High mitotic activity – rapid rate of growth
- Invasion of surrounding tissue
- Metastasis – cause multiple organ failure
What is tumour staging and grading?
Grading – how bad it looks
Staging – how far its got
Tumour grading:
- An assessment of the degree of differentiation of a tumour
- Correlates with how aggressive it behaves
- Only for malignant tumours
Tumour staging: Based on three main features - Size of primary tumour - Extent of lymph node disease - Any blood-borne metastasis Sometimes quoted as ‘TNM’ (tumour, node, metastasis)
The TNM system
T = size of tumour (T1 to T4)
N = extent of lymph node involvement (N0 to N3)
M = distant metastasis (M0 to M1)
- Criteria different for each tumour
- Better prediction of outcome than grade, for most tumours
Explain the significance of the oestrogen receptor. Where is it present? what does oestrogen do to it? what does this complex do? what happens in breast cells?
- Oestrogen receptor present in the nucleus of certain target cells in the body
- Oestrogen molecule enters passes through the target cell’s membrane and enters the nucleus
- Oestrogen binds to its complementary receptor in the nucleus
- The shape of the receptor changes
- Oestrogen-receptor complex then binds to specific DNA sites, called oestrogen response elements, which are located near genes that are controlled by oestrogen
- Oestrogen-receptor complex binds to coactivator proteins and more nearby genes become active
- Hepatocytes: oestrogen increases the amount of HDL cholesterol and decreases the amount of LDL cholesterol
- Breast cells: oestrogen causes cell proliferation of the cells lining the milk glands, thereby preparing the breast to produce milk if the woman should become pregnant – then oestrogen levels deplete at the end of the menstrual cycle, these cells deteriorate and die
- Bones: regulate bone formation (osteoblasts) and bone resorption (osteoclasts) and epiphyseal plate closure
- Uterus: growth of endometrium in menstrual cycle
What is the importance of this ER receptor in breast cancer? and what is the treatment for breast cancers that are ER positive?
- Mutation of a gene that controls proliferation occurs
- This could be that of a proto-oncogene or tumour suppressor gene
- This mutation is passed down to the daughter cells
- Later, more mutations in these altered cells can lead to uncontrolled proliferation and the onset of cancer
- Oestrogen doesn’t cause the mutation, oestrogen increases the rate of proliferation of cells (even the mutated cells possessing the ER)
- This increases the total number of mutant cells
- These cells are at an increased risk of becoming malignant, so the chances that cancer may actually develop increases
- Treatment: tamoxifen
Describe how the progesterone receptor (PR) works. What is the treatment?
- Progesterone receptor found in the cytoplasm of target cells
- When no binding hormone is present the carboxyl terminal inhibits transcription
- When progesterone binds to the receptor, there is a structural change that removes the inhibitory action
- After progesterone binds to the receptor, restructuring with dimerization follows and the complex enters the nucleus and binds to DNA
- Transcription takes place, resulting in formation of messenger RNA that is translated by ribosomes to produce specific proteins
- Treatment: progesterone antagonists, antiprogestins
Describe the human epidermal growth factor 2 receptor (HER2). How does it work? what does it cause?
- There are 4 HER: HER1, HER2, HER3, HER4
- Growth factors (ligands), bind to either HER1, HER3 or HER4
- This causes them to dimerise with either another receptor that is the same as it or another receptor from the HER family
- HER2 is called an ‘orphan receptor’ because it does not bind to a ligand
- HER2 dimerises with ligand-bound HER1, HER3 or HER4
- Receptor dimerization activates signalling pathways inside the cell
- These pathways lead to cell growth, proliferation, and survival – this is done by activating the protein cyclin D1
