Molecular Basis of Breast Cancer

Question 1

What is one of the primary risk factors for breast cancer?

Answer 1

hormones that come in cycles; early pregnancy would be a “protective” risk factor - they do not know for sure but this is an example of non-cyclic hormone production

Question 2

how is breast cancer detected?

Answer 2

mammogram (2D or 3D), MRI (most sensitive - use with high dense tissue) and ultrasound (used a complement to mammogram and MRI)

Question 3

when a lump is found, what is done next?

Answer 3

biopsy the lump (fine needle, core-needle, or surgical)

then will determine if the sample is malignant, the Grade and what receptors are present

Question 4

what receptors could be present in a biopsy? why do we care?

Answer 4

Estrogen receptor (ER), progesterone receptor (PR) and/or Her2/neu

we care because these receptors can determine the treatment type

Question 5

what are the histologic types of breast cancer? which one is the most common? which one is the hardest to treat?

Answer 5

ductal, mixed tumor, inflammatory, mucinous, and lobular

invasive ductal carcinoma (IDC) - most common

inflammatory - hardest to treat because it is not diagnosed until later stages and the tumors are spread throughout the breast

Question 6

what is the primary source of hormone production in post-menopausal women? why is this important?

Answer 6

fat - breasts are very fatty and now obesity is considered to be a high risk factor for women

Question 7

what is the precursor to the most common form of breast cancer? describe the stage, if it is malignant/benign, how it is detected and what will happen to these precursors.

Answer 7

ductal carcinoma in situ (DCIS) = precurosr to invasive ductal carconoma (IDC)

stage 0, malignant, detected mostly by mammogram

50% of DCIS will not progress to IDC but 30% will recur after lumpectomy as IDC

Question 8

what are the primary metastatic sites for breast cancer?

Answer 8

lymph - 88%, bone - 19.6%, liver - 12.2%, lung - 12.1%, brain - 1.7%

Question 9

describe breast cancer survival rates by stage.

Answer 9

0: 100%
1: 98%
2: 88%
3: 52%
4: 16%

Question 10

what are the major genetic players in breast cancer?

Answer 10

ER/PR, Her2/neu, BRCA1/2

Question 11

describe how ER/PR can influence breast cancer.

Answer 11

ER/PR: steroid-activated nuclear receptors; breast tissue is very responsive to these hormones

these are located in the cytoplasm (when ligand not present); when ligand binds, goes to nucleus and activates genes that are pro-proliferative and pro-survival; ER can bind directly to DNA via ERE (estrogen receptor elements) or bind to other TF already bound to DNA

note: can also turn off genes and turn on anti-apoptotic genes

can interact with transmembrane proteins to help turn on pathways that also activate survival/growth genes (survival: AKT/mTOR pathway and growth: MAPK)

Question 12

how does Her2/neu influence breast cancer? how can you tell if it is Her2/neu?

Answer 12

her2/neu: receptor tyrosine kinase (so on the plasma membrane)

other namesL ERBB2 and EGFR2

typically have a genomic amplification (multiple Her2 genes) and overexpression (many Her2 receptors) which leads to many more receptors on the cell surface. the increase in concentration of these receptors increases the probability for autophosphorylation in the absence of ligand -> have uncontrolled proliferative effects

can tell it is Her2/neu by using immuno-histochemistry or FISH

Question 13

how does BRCA1/2 affect breast cancer? what are the specific roles of each gene?

Answer 13

BRCA1: senses/recognizes the DNA damage and regulates cell cycle progression

BRCA2: helps cell repair the DNA

lots of cross talk between BRCA1/2 and ER/PR -> tissue specificity

*some controversy, but together they are involved in sensing and repairing the DNA damage…contribute to genomic instability of the tumors

these are high penetrance genes and account for 25% of the 10% hereditary breast cancer; if have a mutated BRCA1/2, have a higher risk for breast and ovarian cancers

Question 14

what population has a high frequency of BRCA1/2 mutation and what are these mutations?

Answer 14

Ashkenazi Jewish

BRCA1: 187delAG and 5382insC
BRCA2: 6174delT

Question 15

what are the molecular subtypes of breast cancer? why do we care? how are they found?

Answer 15

luminal A: ER+/PR+ -> luminal cells
luminal B: ER+/PR+/- -> luminal cells
ErbB2/Her2 (Her2+) -> not categorized on cell phenotype
Basal (triple negative: ER-/PR-/Her2-) -> basal/myoepithelial cells
Normal

these are independent predictors of survival and can be used to have a more targeted treatment

found by gene expression profiling

Question 16

what kits are used for gene expression profiling? why do we care?

Answer 16

Oncotype DX and PAM50: accepted as a predictive and prognostic test

MammaPrint: accepted as a prognostic test

oncotype RS score will determine how likely a patient is to get cancer again - only helpful in stage 0-2 (low = better)