Molecular Cloning of BIG3 Gene in Breast Cancer

Running head: DISSERTATION
Literature review
Name of the Student
Name of the University
Author Note

DISSERTATION1
Chapter 2: Literature review
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
(Miller et al. 2016). 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 (Abu-Helalah et al. 2015).
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 micro metastasis. 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 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.

DISSERTATION2
(Freag 2017) The primary aim of treatment is to regulate and reduce down the spread of
cancerous cells to the brain.
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. Investigations regarding prognostic factors indicate that tumour 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
the implication of cell-surface glycosylation in metastatic interactions between different
organs (Vajaria et al. 2016).

DISSERTATION3
Loss of expression of GALNT9 (O-glycosylation initiator), CCDC8 (microtubule dynamics
regulator) and BNC1 (transcription factor) can contribute to the progression of primary breast
tumors to brain metastases (Pangeni et al., 2015).
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 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 (Chigira et al. 2019). 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.
Figure 1- ARFGEF3 Gene in genomic location
Source- (Gene Cards 2019)
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