HER-2 Positive Breast Cancer

Running head: HER-2 POSITIVE BREAST CANCER
HER-2 Positive Breast Cancer
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Introduction
HER-2 positive breast cancers are characterized by a mutation in Human epidermal
growth factor Receptor 2 (HER-2) which shows a manifestation of tumor growth through
excessive cellular growth and proliferation. Mutations in HER-2 gene result in aggressive
form of breast cancers. Recurrence of breast cancers can be a sign of HER-2 overexpression
(Kümler, Tuxen and Nielsen 2014). The precise causative factors of breast carcinomas are
debatable and yet doubtful. Still, breast cancer risks in women increases through increased
exposure to hormones like estrogen and progesterone. More estrogen in cellular system
increases the susceptibility of women to breast cancers.
HER-2 positive breast cancer
Human Epidermal growth factor Receptor (HER) is a family of receptors which
consist of four members such as HER-1, hER-2, HER-3 and HER-4 which are also
recognized as ErbB1, ErbB2, ErbB3 and ErbB4 respectively. The pathogenicity of breast
cancer shows the involvement of HER-2in inducing carcinogenicity of mammary glands. The
amplification of HER-2 gene leading to overexpression has been found in 15-30 % of
reported breast cancers (Kümler, Tuxen and Nielsen 2014). HER-2 has been found to be
present in multiple copies in breast cancers; the expression of HER-2 gene leads to increased
protein expression which in turn leads to multiple receptors to be expressed on the tumor cell
surface. The estrogen binds to its estrogen receptor and brings about activation of HER-2
signaling cascade. The progression of breast cancer from stage I to stage III has been
correlated with increased overexpression of HER-2 in case of invasive metastasis (Kümler,
Tuxen and Nielsen 2014). P95 is an abnormal form of Her-2 which has been found to be
constitutively active in breast cancers; this aberrant p95 form of HER-2 lacks the
extracellular domain. Her-positive breast cancers have an aggressive form of carcinogenicity

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compared to HER-2 negative breast cancers. Her-2 overexpression leads to uncontrolled
cellular growth and proliferation, finally leading to cancerous development.
Signaling
HER family of receptors lead to downstream signaling cascade through receptor
homodimerisation or heterodimerisation, ultimately leading to increased cellular growth and
proliferation. HER-2 with its kinase domain remains present in an open conformation; HER-2
dimerises with either HER1 or HER-3 and activates the PI3K and AKT downstream
signaling which further activates Raf and MAPK signaling pathways. HER2 itself cannot
activate PI3K/Akt signaling pathway in tumor progression; dimerisation of HER-2 with
HER-3 causes an open conformational state exposing the extracellular dimerisation domain
(Paplomata and O’Regan 2014). This indirect mechanism of HER2-HER-3 dimerisation
takes place through second messenger pathways like Grb2 and Ras signaling activation.
HER2-HER-3 dimerisation causes phosphorylation of tyrosine kinase domains in plasma
membrane; the Grb2 adaptor molecule bind sto phosphorylated tyrosine kinase and activates
Ras protein through exchange of GDP to GTP state. This activated PI3K causes transfer of
phosphate groups from PIP2 to PIP3 and ultimately leading to Phosphatidyl inositol 3,4,5
triphosphate formation. PIP3, anchored to the plasma membrane, binds to the plextrin
homology (PH) domain of Akt, causing its activation (Yang, Polley and Lipkowitz 2016.).
This allows translocation of Akt from plasma membrane to cytosol, followed by
conformational changes and phosphorylation of threonine 308 by PDK1 and serine 473 by
PDK2. Akt then enters into nucleus and performs transcription regulation of proteins through
phosphorylation.
HER-2 receptor dimerisation causes phosphorylation of tyrosine residues on the
cytoplasmic kinase domain. Docking proteins like grb2 binds to these phosphorylated

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tyrosine residues through Src homology domains or SH2 domains and involves nucleotide
exchange factor SOS . Grb2-SOS promotes the exchange of GDP for GTP in Ras. GTP
bound state causes activation of Ras (Medford et al. 2018). Activated Ras causes activation of
RAF kinase, which undergoes phosphorylation and activates MEK; phosphorylation of MEK
kinase activates the Mitogen-activated protein kinase (MAPK pathway).
Differential diagnosis of her2 positive breast cancer
ImmuniHistoChemistry (IHC) technique determines the presence and amount of
proteins (HER2) through using labeled antibodies specific to the protein of interest. The
labeled antibody binds to the target protein (HER-2) and appears darker under microscopic
observation. A scoring system with a score of 3+ indicates overexpression of HER-2 (Wolff
et al. 2013). Fluorescence In-situ Hybridisation (FISH) technique provides genetic mapping
of the breast cancer tissue which is removed during biopsy. FISH helps to check for the