Molecular Cloning of BIG3 Gene Associated with Secondary Breast Cancer in the Brain

This dissertation explores the molecular cloning of the BIG3 gene and its association with secondary breast cancer in the brain. It discusses the incidence of brain metastases, genetic drivers, and potential treatment options. The study emphasizes the need for further research in this area to improve the understanding and management of secondary breast cancer in the brain.

Running head: DISSERTATION
Introduction
Name of the Student
Name of the University
Author Note

1DISSERTATION
Introduction
Breast cancer refers to the cancer that generally develops in the breast tissue and the
common signs and symptoms of this condition comprise of lump development in the breast,
change in shape of the breast, fluid ejection from the nipple, or scaly red patch on the skin.
Time and again it has been found that major risk factors that are responsible for the
development of breast cancer comprise of reduced physical activity, alcohol consumption,
obesity, hormone replacement therapy, and/or early menstruation age (Neuhouser et al.
2015). Secondary breast cancer, also referred to as metastatic breast cancer refers to stage IV
of the disease where the cancerous cells have spread to sites that are distant from the breast,
farther than the axillary lymph nodes (DeSantis, Ma, Bryan and Jemal 2014). Currently, no
cure has been discovered for secondary breast cancer. It typically occurs more than a few
years after diagnosis of the primary breast cancer, though it is occasionally diagnosed at the
similar time or, seldom, prior to diagnosis of primary breast cancer.
Discussion
Research evidences elaborate on the fact that breast cancer predominantly
metastasizes to the lungs, bone, liver, regional lymph nodes, and the brain, with bone being
one of the most common region (Aceto et al. 2014). Treatment of secondary breast cancer is
dependent on the site of the metastatic tumours and encompasses several means such as,
radiation, surgery, biological therapy, chemotherapy, and hormonal therapy. The brain has
been identified as a unique organ where breast cancer metastasis occurs owing to the fact that
the tumour cells have to cross the blood-brain barrier for development of micrometastasis.
According to Chen and Bourguignon (2014) CD44 is a cell-surface transmembrane
glycoprotein that acts as a hyaluronic acid specific receptor that is responsible for cell
adhesion, which in turn is brought about by binding to particular components of the

2DISSERTATION
extracellular matrix. In addition, CD44 also controls adhesion of the breast cancer cells that
are circulating in the brain, at the secondary site to the endothelium, via the hyaluronate
matrix ligand and/or cytoplasmic attachments. Therefore, the primary aim of treatment is to
regulate and reduce down the spread of cancerous cells to the brain.
Leone and Leone (2015) highlights breast cancer as the common cause of brain
metastases and it is a catastrophic event for patients as it is associated with poor prognosis
and survival of patient. The investigating regarding prognostic factors indicate that tumor
subtypes is a prognostic factor that influences overall survival rate. Another prognostic factor
is the performance status of patients at the time of diagnosis of brain metastases. Some of the
local therapy modalities available for the treatment of brain metastasis include surgical
resection, stereotatic radiosurgery and the whole brain radiation therapy. The advantage of
surgical therapy is that it is associated with improvements in focal deficits and decrease in
intracranial hypertension. In contrast, whole brain radiation therapy plays a role in controlling
macroscopic metastases. However, as brain metastases represent at unmet need in breast
cancer patient, a better understanding of the molecular underpinnings of CNS progression is
needed in future.
According to the "seed and soil" hypothesis particular organs trigger metastases from
one kind of cancer by promoting their proliferation and growth, when compared to other
cancer types. This interaction is generally found to be reciprocal and dynamic, owing to the
capability of the cancer cells to transform the environment where they are present (Liu et al.
2017). Hence, this hypothesis considers tumour embolus as the seed and suggests that the
target organs that are affected by cancer act as the substratum or soil. Secondary breast cancer
in the brain has also been associated with cell-surface sialylation that results in cell–to-cell
interactions. This mechanism is directly responsible for the over-expression of
sialyltransferase in the breast cancer cells that are located in the brain, thereby highlighting

3DISSERTATION
the implication of cell-surface glycosylation in metastatic interactions between different
organs (Vajaria et al. 2016). BIG3 (Brefeldin A-inhibited guanine nucleotide-exchange
protein 3) is a gene that is responsible for the activation of ARF protein, which in turn is
mediated by the exchange of free GTP for bound GDP. This gene plays a significant role in
nuclear fusion and nuclear division phase and has often been associated with breast cancer
(Yoshimaru et al. 2014). BIG 3 is a tumor suppressor gene that plays an important role in
estrogen signalling regulation and it binds to cancer protein and prohibitin 2 (PHB2) to
suppress estrogen dependent transcriptional activities. Hence, inhibition of the BIG3-PHB2
interaction can become a novel treatment for breast cancer (Katagiri, Miyamoto & Hayashi,
2019). However, understanding the molecular cloning affects secondary breast cancer of the
brain needs to be explored.
. In view of the adverse impact of breast cancer progression from primary to the
secondary, Han and Brastianos (2017) gave details regarding the genetic characterisation of
brain metastases. The study emphasized on molecular characterization of the cancer so that
effective treatment option could be identified. The study pays special attention to genetic
profiling of brain metastases and the management of brain metastases resulting from cancer
of the breast, lung, kidneys and ovaries. Past research paid special attention to characterize
genetic drivers in the brain. However, research in this area in this area is still going on and
better understanding of the molecular changes associated with secondary breast can help in
better evaluation of brain metastases and knowledge of targeted therapies. Breast cancer is
the most common form of cancer and the exact mechanism leading to brain metastases is
unknown. One study evaluating the cumulative incidence of CNS relapse revealed human
epidermal growth factor receptor 2 (HER2) positive breast cancers as a major risk factor
behind brain metastases. Early occurrence of brain metastases from breast cancer is
associated with early onset tumor. Survival of patient is also found to be dependent on

4DISSERTATION
presence of ER positive tumor types Hence, this finding gives the implication that survival
outcomes for breast cancer patient is affected by different subtypes of breast cancer.
Another molecular study highlights the role of epidermal growth factor (EGFR)
mutations on cumulative incidence of brain metastases too. The study compared cases or
incidence of brain metastases in patients with EGFR compared to patients with EGFR wild
types. The study revealed that mutation in the EGFR gene renders the tumor sensitive to the
EGFR tyrosine kinase inhibitor. The ultimate impact of such mutation is that it enhances the
chance of survival for patients. Due to positive CNS activity, including EGFR TKIs in the
treatment of brain metastases can be a novel treatment options in the future (Helena et al.,
2013). However, before these molecular mutation is confirmed as a pathway for effective
treatment, there is a needed for prospective investigations of the role of EGFR TKIs in active
brain metastases particularly for primary breast cancer transitioning to secondary breast
cancer to the brain.
Conclusion:
From the review of the incidence of secondary breast cancer in the brain and
molecular link behind the occurrence of brain metastases, it can be concluded that various
molecular links and mutations has been found to influence the condition. Strong evidence for
the role of EFRR TKIs in cancer survival has been found. However, this has not been done
for breast cancer patients with secondary breast cancer to the brain. As BIG3 has been found
to play a major role in growth of the brain, conducting future research on the impact of this
gene on cancer development is needed. This research is focused on evaluating the impact of
molecular cloning of BIG3 (ARFGEF3) Gene associate with secondary Breast Cancer in the
Brain.

5DISSERTATION
References
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