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Page 2 of 15 Hadadi et al. J Cancer Metastasis Treat 2018;4:25 I http://dx.doi.org/10.20517/2394-4722.2018.22

Keywords: Breast cancer, papaya leaves, antioxidants, polyphenols

INTRODUCTION
[1]
Cancer is the second most common cause of death in the US About 1,685,210 people were estimated
.
[2]
to have been diagnosed with cancer, and an estimated 595,690 were expected to die from it in 2016 .
According to a published report, an estimated 14 million cases of cancer reported worldwide and nearly half
[3]
(about 13% of the total worldwide deaths) died from cancer . According to National Cancer Institute (2016),
the most common cancer in the world is breast cancer in females and prostate cancer in males, followed
[4]
by lung cancer. However, lung cancer causes more deaths than breast or prostate cancer . Breast cancer
is characterized in different molecular phenotypes based on three cellular receptors: estrogen receptor
(ER), progesterone receptor (PR), and the epidermal growth factor receptor family member (Her-2/Neu).
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According to this classification a breast cancer can be ER /PR /Her-2 , ER /PR /Her-2 , ER/PR/Her-2 , or
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+
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+
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+
+
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-[5]
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ER/PR/Her-2 . These subtypes have different tumor biology and treatment strategies.
The early and advanced hormone positive breast cancers can be effectively treated with endocrine therapy
[6]
which blocks the estrogen production and/or inhibits the effect of estrogen at the receptor level . Tamoxifen
is a selective modulator of ER which is used as a gold-standard adjuvant treatment since 1995 for pre-and
postmenopausal patients at low-risk of recurrence . More recently, aromatase inhibitors (AIs) including
[7]
drugs letrozole, anastrozole, and exemestane are developed which inhibit enzyme aromatase and reduce
estrogens formation from androgens . Other recent developments in breast cancer therapy include the
[8,9]
development of strategies to inhibit Her-2 activity, especially in Her-2 positive breast cancer by monoclonal
antibodies and by antibody fragments [10,11] . The recently developed humanized monoclonal antibody,
trastuzumab (Tra), specifically targets the extracellular domain of Her-2, which is approved by the Food
and Drug Administration (FDA) for the treatment of Her-2 breast cancer [12,13] . Another strategy to treat
+
breast cancer is to develop inhibitors for angiogenesis. Angiogenesis is a process where new blood vessels are
formed from existing vessels . The strategies to reduce angiogenesis are (1) the development of antibodies or
[14]
small molecules against vascular endothelial growth factor, basic fibroblast growth factor or platelet-derived
growth factor to inhibit action of these proangiogenic factors and (2) the use of endogenous angiogenesis
inhibitors including thrombopondin-1, endostatin, angiostatin, arresten, canstatin and tumstatin [15,16] .
Although successful, these treatments for breast cancer have considerable side effects and often patients
develop resistance to these drugs. There is a growing interest to use natural products for as an alternative or
adjunct strategy to treat and prevent breast cancer.
Several epidemiological studies have shown that consumption of fruits, and vegetables (especially soy and
cruciferous vegetables) are linked to reduced risk of breast cancer [17,18] , and some dietary natural products
consumption might increase the survival rate of breast cancer by reducing the recurrence [19,20] . Several
experimental studies have also shown that dietary natural products and their bioactive compounds can be
very effective in reducing breast cancer growth because they are able to downregulate ER-α expression and
activity; inhibit tumor proliferation, metastasis and angiogenesis of breast tumor cells; induce apoptosis and
cell cycle arrest; and sensitize breast tumor cells to radiotherapy and chemotherapy [21,22] . It has been shown
that the breast carcinogenesis occurs due to oxidative damage of mitochondrial DNA by reactive oxygen
species (ROS) [23,24] . In a review article, studies were discussed indicating that the effects on cancer cells by
fruits and vegetables, which are rich in flavonoids and other phenolic compounds, have been associated with
their abilities to reduce or inhibit free radical-mediated damage to cellular macromolecules, such as proteins,
[25]
lipids, and DNA . These observations suggest that there may be an inverse association between anti-
oxidation properties and cancer cell growth. The consumption of natural-dietary substances is, therefore,
[26]
suggested as a useable approach for the prevention and/or treatment of breast cancer .