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Hadadi et al. J Cancer Metastasis Treat 2018;4:25 I http://dx.doi.org/10.20517/2394-4722.2018.22 Page 13 of 15
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cells were largely unaffected. To further validate this finding, AU565, another ER breast cancer cell line,
was used. Similar to Sk-Br-3, water extract of papaya leaves also inhibited growth of this cell lines. These
data, therefore, confirm the effect of water extracts from leaves on ER subtypes of breast cancer, which
are difficult to treat. This observation indicates that water-soluble, small molecular weight compounds
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present in papaya leaves may be responsible for the anticancer activity in ER breast cancer cell lines.

It is also interesting to note that both seeds and leaves extracts were similar in their anti-oxidation activity;
however, leaf extracts inhibited ER breast cancer cell growth more potently than that of seeds extracts. It
is clear from this observation that the antioxidation activity may not have attributed to their anticancer
activity. Our results are consistent to other studies where growth inhibition of MCF-7 cells by pomegranate
[44]
extract was not attributed to its high antioxidant potential . It appears that the inhibitory compounds in
the water extract of papaya leaves acted on cellular mechanism that are involved in regulating cell growth.
During the present investigation, the phenolic composition of water extracts of leaves was not determined.
However, it has been shown that papaya leaves extract contained proanthocyanidins and saponins classes
of phenolic compounds. Water extract of papaya is commonly consumed to prevent/treat other diseases in
[45]
traditional medicine . This observation suggests that consumption of papaya leaf extract is probably safe.
Furthermore, our data are consistent with previous studies, suggesting that papaya leaves can be beneficial
[35]
for a number of cancers including breast cancer .

Our data is interesting because ER or triple negative tumors have limited options for the treatment. Triple-
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negative breast cancers do not have estrogen, progesterone, or Her-2 receptors and treatment with drugs
designed to interfere hormone activities is not effective in these receptor-negative cancer cells. These cancers
often grow faster than receptor-positive breast cancers. In most cases pre-menopausal women develop
hormone receptor-negative cancers and appears to be common in younger women and in women with
-
[46]
African-American or Hispanic/Latina ancestry . Some of the ER breast cancers are Her-2 positive that
[47]
-
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cancer are now effectively targeted with Herceptin, which is an antibody for Her-2 proteins . The ER/Her-2 breast
cancers do not benefit from anti-estrogen and/or anti-Her-2 based therapy. The options for treating such
[48]
cancer are limited and involved surgery or chemotherapy, or both . The drugs that are used to target such
tumors are based on inhibition of cell proliferation pathways. Drugs including taxanes, anthracyclin, acts
[49]
on DNA repair complex like, anti-oncogene P53, and stabilizing microtubules . The effect of papaya leaves
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water extracts on ER breast cancer cells in our study appears to be at a moderate level. However, the extract
can be concentrated for more aggressive effects. In addition, papaya leaves extracts can be used as an adjunct
therapy with the generally prescribed anti-cancer drugs, which may improve the efficacy of the drugs and
also reduce the side effects and drug resistance in breast cancer patients. Furthermore, our in vitro data
needs to be validated in an in vivo animal model.
In conclusion, water extract of papaya leaves containing water soluble polyphenols may have a potential to
inhibit ER breast cancer. However, further studies are required to determine the actual chemical nature of
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these phenolic compounds and their mechanism of action.

DECLARATIONS
Authors’ contributions
Concept and design: Siddiqui RA, Rafei R
Manuscript preparation, editing, and review: Siddiqui RA, Kaseloo P, Witiak SM
Experimental studies, data acquisition, data analysis, statistical analysis: Li H, Hadadi SA

Data source and availability
Data were obtained in Food Chemistry and Nutrition Science Laboratory, Agricultural Research Station,
Virginia State University, Petersburg, VA 23806. The data are available in electronic format as Excel and
Sigma plot files upon request.