الفهرس 
Breast cancer
Autophagy and triple negative breast cancerOnly 14 pages are availabe for public view
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Abstract
Breast cancer is one of the highly severe human health
problems and the second deadliest tumor among women. The
treatment strategy of breast cancer is still challenging and need
further research because breast cancer is a heterogeneous disease
with intrinsic subtypes (Zhu et al., 2017; La et al., 2019).
Among the breast cancer subtypes, the triple-negative breast
cancer (TNBC) subtype that is clinically negative for expression of
estrogen, progesterone receptors and human epidermal growth factor
receptor 2 (ER-, PR-, HER2-) is the most aggressive form. Although
massive efforts have been exerted to improve breast cancer
treatments, TNBC subtypes exhibit low survival rate with developing
resistance to chemotherapy (Lefort et al., 2014).
Autophagy “self-eating” is a critical intracellular catabolic
process whereby the cell recycles parts of its own content. It plays a
pivotal role in balancing the cellular sources of energy during normal
and stressful conditions (Khandia et al., 2019).
Autophagy is a cellular housekeeping process which removes
mis-folded or aggregated proteins and clears damaged organelles
through a lysosome-dependent pathway. These cellular damaged
parts are sequestered and sent into the lysosome for degradation and
recycling. It is commonly considered as a survival process, despite its
dysregulation has been related to cellular death (Tripathi et al.,
2019; Poillet-perez et al., 2020).
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CHAPTER I: INTRODUCTION AND AIM OF THE WORK
Autophagy process exists at basal levels in all cells and is
enhanced as a result of various metabolic and oxidative stressful
events, thus occurs in the normal and tumor cells for providing the
cell with nutrients and maintaining energy homeostasis. Despite the
positive effect of autophagy on normal cells survival, autophagy
impact on tumorigenesis and cancer chemosensitivity remains elusive
(Lefort et al., 2014; Maycotte and Thorburn, 2014).
Given autophagy’s pivotal function in tissue homeostasis, so
the dysregulation of autophagy process has been contributed to
various diseases such as tumors, the role of autophagy in cancer is of
a particular interest, and the work in this area has greatly expanded
over the past several years (Amaravadi et al., 2016; Tilija et al.,
2020).
Although the impact of autophagy in cancer is still complicated
and unclear, a promising novel therapeutic target in various breast
cancer types has been shown, playing a ‘double-edged sword’ role,
via increasing or inhibiting treatment efficiency in a context- and
cell-type-dependent manner (Zhou et al., 2016).
The antimalarial agent chloroquine (CQ), is a classic
autophagy inhibitor, blocks the binding of autophagosomes to
lysosomes and results in accumulation of a large number of damaged
proteins in the cytoplasm and induces stresses that eventually result
in cell death (Baoxing et al , 2018).
Autophagy process is vital to enhance the TNBC growth; so
that the inhibition of autophagy process in this subtype may provide
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CHAPTER I: INTRODUCTION AND AIM OF THE WORK
promising therapeutic approaches to enable more effectual
combinatorial therapeutic strategies (Kimmelman and White, 2017).
Lovastatin (LOVA) is a statin -lipid regulating drug- which acts
as 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase
competitive inhibitor. Besides its role in improving cardiovascular
functions, LOVA has proven to have antitumor effects, as well.
Various studies have exhibited the anti-proliferative, anti-angiogenic,
anti-metastatic and pro-apoptotic effect of LOVA treatment and
consequently the effect of LOVA in induction of autophagy in a
variety of cancers (Klawitter et al., 2010; Zhang et al., 2013; Yang
et al., 2016).
Omega-3 polyunsaturated fatty acids (PUFAs) are natural
products beneficially influence cardiovascular functions either alone
or in combination to statin treatments (Alfaddagh et al., 2019). Many
studies have elucidated the antitumor effect of omega-3 PUFAs that
attenuate cancer progression and promote cell death (Pizato et al.,
2018).
Whereas omega-3 PUFAs have been proven to improve the
effect of chemotherapeutic drug therapy, their administration also,
has shown to enhance the autophagy process in the cancerous cells,
as well (Gelsomino et al., 2013; Shin et al., 2013).
While LOVA and DHA have been proven to induce autophagy
process and are clinically used in improving cardiovascular functions
either alone or in combination, their antitumor activities in the
presence and absence of CQ, as an autophagy inhibitor, open a new
research area in repurposing of these drugs in the treatment of TNBC