TBL Breast Mass

Question 1

Growth factors

Answer 1

Capable of stimulating cell growth, proliferation, and differentiation

Question 2

Epidermal growth factors (EGF) (function and structural features)

Answer 2

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.

Question 3

What happens when EGF binds to EGFR? (3 steps)

Answer 3

1. 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

Question 4

Mitogenic response

Answer 4

Cell proliferation in reponse to mitogens

Question 5

Mitogen

Answer 5

Chemical that triggers mitosis by activating signal transduction pathways in which mitogen-activated protein kinase (MAP kinase) is involved

Question 6

ErbB family of receptors

Answer 6

EGFR (aka HER1, ErbB-1), HER2/c-neu (aka ErbB-2), HER3 (aka ErbB-3), HER4 (aka ErbB-4)

Question 7

HER2 vs HER2

Answer 7

If not in italics referring to the protein, if in italics referring to the gene

Question 8

Proto-oncogene

Answer 8

Normal gene which regulates cell growth

Question 9

HER2 (gene)

Answer 9

Proto-oncogene on chromosome 17. Considered an oncogene when it leads to transformation for cells and uncontrolled cell growth.

Question 10

HER2 (protein) names

Answer 10

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).

Question 11

Overexpression of HER2 (prevalence in breast cancer and consequences)

Answer 11

Happens in ~15% of breast cancers. Causes increased signal transduction resulting in rapid cell division and tumor growth.

Question 12

HER pathway

Answer 12

1. 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

Question 13

How is the HER signaling cascade inactivated? (2 ways)

Answer 13

1. 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

Question 14

HER2 (gene) in normal cells

Answer 14

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.

Question 15

HER2+ mutation

Answer 15

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.

Question 16

Oncogene

Answer 16

Gene that has the potential to cause cancer if mutated or expressed abnormally

Question 17

Most common sites of metastasis in breast cancer

Answer 17

Lymph nodes near breast, bones, liver, lungs, and brain

Question 18

Composition of metastatic tumors

Answer 18

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)

Question 19

Breast Cancer Stage 0

Answer 19

Carcinoma is in situ and non-invasive (ex. ductal carcinoma in situ: abnormal cells in the lining of a duct)

Question 20

Breast Cancer Stage 1

Answer 20

Early stage of invasive breast cancer. Cancer cells have not spread beyond breast.

Question 21

Breast Cancer Stage 2

Answer 21

Tumor is 2-5cm and has spread to lymph nodes under the arm

Question 22

Breast Cancer Stage 3

Answer 22

Locally advanced cancer. Tumor has spread to underarm lymph nodes and to lymph nodes behind the breastbone

Question 23

Breast Cancer Stage 4

Answer 23

Distant metastatic cancer. Cancer has spread to other parts of the body (bone, liver, lungs)

Question 24

Recurrent cancer

Answer 24

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.

Question 25

How did researchers develop Herceptin (trastuzumab)?

Answer 25

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.

Question 26

Mechanism of Herceptin (trastuzumab)

Answer 26

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.

Question 27

Herceptin and the immune system

Answer 27

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.

Question 28

Herceptin and chemotherapy

Answer 28

Drug immune response may cause chemotherapy to be enhanced. Herceptin also prevents DNA repair following DNA-damaging chemotherapy which stops turmor cells from growing.

Question 29

2 methods of testing for HER2 mutation

Answer 29

Fluorescence in-situ hybridization (FISH) and Immunohistochemistry

Question 30

Fluorescence in-situ hybridization (FISH) for HER2

Answer 30

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.

Question 31

Immunohistochemistry for HER2

Answer 31

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

Question 32

ER and PR analysis in breast cancer

Answer 32

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)

Question 33

Tamoxifen

Answer 33

Estrogen receptor antagonist

Question 34

Adjuvant therapy

Answer 34

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

Question 35

Neoadjuvant therapy

Answer 35

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.

Question 36

Anthracycline (3 uses)

Answer 36

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

Question 37

Taxol

Answer 37

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.

Question 38

What is special about the HER-2 structure?

Answer 38

HER2 requires no ligand (meaning always in active configuration). HER2+ is considered an aggressive cancer.