Question

9. Breast cancer can be caused by mutations in a number of different genes.

A. How do mutations in BRCA1 or BRCA2 lead to cancer? Are one or two mutations necessary and can this be inherited? What is the normal function of BRCA1 and BRCA2?

B. What does it mean when a cancer cell is called HER2 positive and why does this lead to cancer? Include in your answer details on the pathway that is altered under this condition and how it changes. Are one or two HER2 mutations necessary and can this be inherited?

C. For one of these two kinds of breast cancer, please explain EITHER how it is diagnosed OR how it is treated.

Answer 1

A. Function of BRCA1 and BRCA2

These genes produce proteins that help in suppressing the tumor. Which means that when there is an error, say a DNA damage happens (a very common phenomenon), these proteins help in recovering the damage and aid the cells to function normally. When there is a mutation in the genes encoding these repair proteins, a shorter version or lesser proteins are produced. As a result when there is a DNA damage, the cells failed to be repaired and lead to a complicated situation where the cells seize to dei (programmed cell death) and becomes a cancerous cell.

These mutations are inheritable and can be inherited from either parents.

B. HER2 positive breast cancer

HER2 (Human Epidermal growth factor Receptor 2) proteins are also known as growth promoting proteins and these proteins are mostly found on the outside of the proteins. When there is increased amount of HER2 produced in the breast cancer cells, this type is referred to as HER2 positive breast cancer.

HER2 activates two major pathways in the cellular system.

1. The RAS pathway

2. THE PIK3CA pathway

When there are increased number of HER2 receotors present on the cell wall, these receptors activates the RAS proteins.

A diagramatic representation of a pathway that involves HER2 and cell proliferation is given below

C) Diagnosis of HER2 positive breast cancer

IHC and FISH testing strategy are the most common type of testing HER2 positive cases. A more advanced technique is to identify the mutations in the HER2 protein using NGS technologies (not cost effective though).

IHC- Immuno Histochemistry Testing: A chemical dye that stains these proteins and based on this scores are given. The score ranges between 0 to 3. A score of 0, 1 is cosidered as negative. A score 2+ is considered as borderline case and a score of 3+ is considered as HER2 positive case.

When the cases are borderline, a next line testing with FISH is done to understand the severity of the case.

FISH- Fluorescence In Situ Hybridization: Much similar to IHC testing, a labelling technique is used which enables the protein to glow in dark. This is not a widely used strategy and time consuming in comparison to IHC. Hence IHC is the first line of testing to identify HER2 positive cases.