TBL Breast Mass Flashcards
Growth factors
Capable of stimulating cell growth, proliferation, and differentiation
Epidermal growth factors (EGF) (function and structural features)
Induce proliferation in epidermal cells. Have high binding affinity for EGFR (epidermal growth factor receptor). Produces mitogenic response (encourages proliferation) in EGF-receptive cells. Have 6 cysteine residues.
What happens when EGF binds to EGFR? (3 steps)
- Stimulates protein-tyrosine kinase activity of receptor 2. This initiates a signal cascade leading to increases in intracellular Ca2+, increases glycolysis and protein synthesis, and increases expression of certain genes (including EGFR gene) 3. DNA synthesis and cell proliferation
Mitogenic response
Cell proliferation in reponse to mitogens
Mitogen
Chemical that triggers mitosis by activating signal transduction pathways in which mitogen-activated protein kinase (MAP kinase) is involved
ErbB family of receptors
EGFR (aka HER1, ErbB-1), HER2/c-neu (aka ErbB-2), HER3 (aka ErbB-3), HER4 (aka ErbB-4)
HER2 vs HER2
If not in italics referring to the protein, if in italics referring to the gene
Proto-oncogene
Normal gene which regulates cell growth
HER2 (gene)
Proto-oncogene on chromosome 17. Considered an oncogene when it leads to transformation for cells and uncontrolled cell growth.
HER2 (protein) names
Named because of similar structure to Human Epidermal growth factor Receptor 2. neu orginally identified in neuroglioblastoma cell lines. ErbB-2 named for similarity to ErbB (avian erythroblastosis oncogene B).
Overexpression of HER2 (prevalence in breast cancer and consequences)
Happens in ~15% of breast cancers. Causes increased signal transduction resulting in rapid cell division and tumor growth.
HER pathway
- EGF binds to EGFR (HER-2 protein) 2. Receptors dimerize and activate tyrosine kinase 3. Ras and MAP kinase are signaled 4. MAP kinase transported to the nucleus where genes are activated leading to mitosis
How is the HER signaling cascade inactivated? (2 ways)
- Remove receptors on the cell through endocytosis and degredation 2. Use an antagonist molecule which will bind to the EGFR receptor but not initiate signal transduction
HER2 (gene) in normal cells
1 copy of HER2 on each copy of chromosome 17. Expression of this gene in normal breast epithelial cells gives rise to transmembrane protein growth factor receptor with tyrosine kinase activity.
HER2+ mutation
HER2 gene amplified 2-20x in each tumor cell nucleus. Amplification drives protein overexpression leading to increased number of receptors at the tumor-cell surface (2 million vs normal 20,000). Receptor activation is promoted leading to signaling, excessive cell division, and formation of tumors.
Oncogene
Gene that has the potential to cause cancer if mutated or expressed abnormally
Most common sites of metastasis in breast cancer
Lymph nodes near breast, bones, liver, lungs, and brain
Composition of metastatic tumors
Has same kind of abnormal cells as primary tumor (if breast cancer cells move to bone it’s still breast cancer, not called bone cancer)
Breast Cancer Stage 0
Carcinoma is in situ and non-invasive (ex. ductal carcinoma in situ: abnormal cells in the lining of a duct)
Breast Cancer Stage 1
Early stage of invasive breast cancer. Cancer cells have not spread beyond breast.
Breast Cancer Stage 2
Tumor is 2-5cm and has spread to lymph nodes under the arm
Breast Cancer Stage 3
Locally advanced cancer. Tumor has spread to underarm lymph nodes and to lymph nodes behind the breastbone
Breast Cancer Stage 4
Distant metastatic cancer. Cancer has spread to other parts of the body (bone, liver, lungs)
Recurrent cancer
Cancer that has come back after a period of time when it could not be detected. It may recur locally in the breast or chest wall or it may recur in any other part of the body.
How did researchers develop Herceptin (trastuzumab)?
Transformed normal genes to cancerous ones by adding HER2 gene showing that HER2 is an oncogene. Designed monoclonal antibody designed specifically for HER2 to block function, making cancer cells grow more slowly.
Mechanism of Herceptin (trastuzumab)
Binds to HER2 protein and blocks signal transduction. Receptors bound to drug are endocytosed and degraded. This reduces cellular response to EGF and reduces cell proliferation.
Herceptin and the immune system
Drug signals the immune system–once drug binds to HER2 natural killer cells of immune system attracted to Herceptin. The drug, in turn, binds to natural killer cells and helps them determine which cells are abnormal to kill them.
Herceptin and chemotherapy
Drug immune response may cause chemotherapy to be enhanced. Herceptin also prevents DNA repair following DNA-damaging chemotherapy which stops turmor cells from growing.
2 methods of testing for HER2 mutation
Fluorescence in-situ hybridization (FISH) and Immunohistochemistry
Fluorescence in-situ hybridization (FISH) for HER2
Gene-based diagnostic test used to identify number of HER2 genes per cell. Ratio of HER2 genes to a reference gene such as CEP17 (chromosome enumeration probe 17) can also be calculated.
Immunohistochemistry for HER2
Protein-based diagnostic test used to identify overexpression of HER2 protein. Amount of protein present in a tumor determined by lab test and assigned a score from 0 (negative) to 3+ (highly positive score). Only patients with high scores expected to benefit from Herceptin treatment
ER and PR analysis in breast cancer
75% of breast cancers are estrogen receptor (ER)-positive, 65% of breast cancers are progesterone receptor (PR)-positive. If ER and PR-positive recommended treatment includes Tamoxifin (blocks binding of estrogen to the ER) and aromatase inhibitors (block estrogen production-used in postmenopausal women)
Tamoxifen
Estrogen receptor antagonist
Adjuvant therapy
Additional treatment, usually given after surgery where all detectable disease has been removed but remains statistical risk of relapse due to occult (not accompanied by readily discernible signs or symptoms) disease
Neoadjuvant therapy
Given before the main treatment (ex. Chemotherapy given before removal of a breast). Most common reason for giving it is to reduce the size of a tumor which will facilitate more effective surgery.
Anthracycline (3 uses)
Chemotherapeutic drug 1. Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA or RNA strand, thus preventing replication of rapidly growing cancer cells 2. Inhibits topoisomerase II activity which blocks DNA transcription and replication 3. Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes
Taxol
Chemotherapeutic drug that is an antimicrotubule agent and considered cell-cycle specific because it acts on cells during cell division. Inhibit the microtubule formation within the cell resulting in cell death.
What is special about the HER-2 structure?
HER2 requires no ligand (meaning always in active configuration). HER2+ is considered an aggressive cancer.
