Question

For the gene BRCA2, identify the normal function of the protein encoded by the gene and how the mutations of the gene causes Breast cancer via the role of the defective protein in the gene. Diagrams are appreciated to demonstrate the following concepts;

1) Signal Transduction - Is it paracrine signalling? I actually don't understand how the kinases work.

2) Cell Division- It is the S phase right but like I don't know how to phrase it

3) Genetics - I know it is Autosomal Dominant but like how to say this???

Answer 1

BRCA1 and BRCA2 are human genes that produce tumor suppressor proteins. These proteins help repair damaged DNA and, therefore, play a role in ensuring the stability of each cell’s genetic material. When either of these genes is mutated, or altered, such that its protein product is not made or does not function correctly, DNA damage may not be repaired properly. As a result, cells are more likely to develop additional genetic alterations that can lead to cancer.

Specific inherited mutations in BRCA1 and BRCA2 most notably increase the risk of female breast and ovarian cancers, but they have also been associated with increased risks of several additional types of cancer. People who have inherited mutations in BRCA1 and BRCA2 tend to develop breast and ovarian cancers at younger ages than people who do not have these mutations.

A harmful BRCA1 or BRCA2 mutation can be inherited from a person’s mother or father. Each child of a parent who carries a mutation in one of these genes has a 50% chance (or 1 chance in 2) of inheriting the mutation. The effects of mutations in BRCA1 and BRCA2 are seen even when a person’s second copy of the gene is normal.

Answer 1- STAT3 can be activated through paracrine signaling in breast epithelial cells. ... BACKGROUND: Many cancers, including breast cancer, have been identified with increased levels of phosphorylated or the active form of Signal Transducers and Activators of Transcription 3 (STAT3) protein.

Cancer-Causing Mutations Affect Signaling Pathways

We can connect the genetic alterations in cancer cells with signaling pathways that control processes associated with tumorigenesis and place these in the context of distortions of wider signaling networks that fuel cancer progression. In each case, the result is dysregulated signaling that is not subject to the normal control mechanisms.

Oncogenic mutations can cause the affected genes to be overexpressed (e.g., gene amplification) or produce mutated proteins whose activity is dysregulated (e.g., point mutations, truncations, and fusions). Examples include proteins involved in signaling pathways that are commonly activated in many physiological responses, such as growth factor receptor tyrosine kinases (RTKs; e.g., the epidermal growth factor receptor, EGFR), small GTPases (e.g., Ras), serine/threonine kinases (e.g., Raf and Akt), cytoplasmic tyrosine kinases (e.g., Src and Abl), lipid kinases (e.g., phosphoinositide 3-kinases, PI3Ks), as well as nuclear receptors (e.g., the estrogen receptor, ER). Components of developmental signaling pathways, such as Wnt, Hedgehog (Hh), Hippo, and Notch can also be affected, as can downstream nuclear targets of signaling pathways—for example, transcription factors (e.g., Myc and NF-κB), chromatin remodelers (e.g., EZH2), and cell cycle effectors (e.g., cyclins).

Alternatively, deletions and other mutations can inactivate negative regulators that normally function as tumor suppressors. Indeed, one of the most commonly mutated genes in cancer is the tumor suppressor p53, the so-called “guardian of the genome.” p53 is a critical hub that controls cell proliferation and stress signals such as apoptosis and DNA damage responses (see below). pRB and CKIs such as p16 are other tumor suppressors whose mutation deregulates the cell cycle. Many tumor suppressors function as negative regulators of cytoplasmic signaling—for example, the adenomatous polyposis coli protein (APC) is a negative regulator of the Wnt pathway, and the lipid phosphatase PTEN is a negative regulator of the PI3K-Akt pathway.

It is worth noting that hyperactivated oncogene pathways can also induce a state of irreversible cell cycle arrest termed senescence (Gorgoulis and Halazonetis 2010; Vargas et al. 2012). This is believed to represent a fail-safe mechanism to inhibit proliferation caused by aberrant activation of oncoproteins in normal cells and is accompanied by changes in cellular structure, chromatin organization, DNA damage, cytokine secretion, and gene expression. Oncogenic transformation requires alterations that abrogate senescence, such as loss of p53 or PTEN.

Oncogenic mutations, amplification, or gene fusions involving upstream tyrosine kinases lead to constitutive signaling through both the Ras-ERK and PI3K-Akt pathways. RTKs including EGFR, ErbB2, fibroblast growth factor receptor (FGFR), and platelet-derived growth factor receptor (PDGFR) are mutated or amplified in a variety of cancers. Similarly, oncogenic mutations in G-protein-coupled receptors (GPCRs) can also activate these pathways.

Answer 2 - Mutations in genes can cause cancer by accelerating cell division rates or inhibiting normal controls on the system, such as cell cycle arrest or programmed cell death. As a mass of cancerous cells grows, it can develop into a tumor.

Cells with intact DNA continue to S phase; cells with damaged DNA that cannot be repaired are arrested and "commit suicide" through apoptosis, or programmed cell death. A second such checkpoint occurs at the G2 phase following the synthesis of DNA in S phase but before cell division in M phase

Answer 3 - In hereditary breast cancer, the way that cancer risk is inherited depends on the gene involved. For example, mutations in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to increase a person's chance of developing cancer

Mutations in this gene are also transmitted in an autosomal dominant pattern in a family. Both BRCA1 and BRCA2 are tumor suppressor genes that usually have the job of controlling cell growth and cell death. Everyone has two BRCA1 (one on each chromosome #17) and two BRCA2 genes (one on each chromosome #13)