PONE-D-20-04206

Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (Tree shrew)

PLOS ONE

Dear Dr. Tsukiyama-Kohara,

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PLOS ONE

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Reviewers' comments:

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Comments to the Author

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Partly

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Reviewer #1: N/A

Reviewer #2: Yes

Reviewer #3: N/A

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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5. Review Comments to the Author

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Reviewer #1: Authors bred and characterized 61 female tree shrews and identified 15 spontaneous mammary tumors. The incidence rate of mammary tumors was 24.6 % (15/61) and the average age of tumor incidence was 2 years 3 months. Unknown inherited factor(s) may paly a role in familial BC. Most cases were simple adenomas and two cases were tubulopapillary carcinomas. Over 90% cases were positive for both ERa and PR. These findings are quite interesting.

Major concerns:

1. Whether pTEN and PI3KCA genes are mutated in these spontaneous mammary tumors should be validated.

2. Ref 25 was incorrectly cited. Additionally, the following ref should be cited: characterization of spontaneous breast tumor in tree shrews (Tupaia belangeri chinenesis), Zoological Research, 2012，Feb. 33(1): 55−59.

3. The pathological differences between this study and Ref 12 should be discussed. Simple adenomas may not be accurate. Please consult pathologist for the classification.

Reviewer #2: Due to their structural differences between mouse and human mammary glands, commonly used mouse models of breast cancer have some limitations. Authors of this manuscript entitled “Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (Tree shrew)” characterized the pathological and genetic aspects of spontaneous mammary tumors in Tupaia belangeri (tree shrew), which shows relatively high genetic homology and structural similarity to human mammary glands. Authors found that the tree shrews in their laboratory have high mammary tumor incidence rate (24.6%) and high rate of simultaneous or metachronous multiplex mammary tumors (60%). Some cases seemed to be of familial mammary gland tumors. Most tumors are benign adenoma and ER+. Two malignant mammary tumors (tubulopapillary carcinoma) were also observed. This work may provide a new animal model for breast cancer research. Future investigation on the genetic basis of familial cases may provide new insight into the mechanism of mammary tumorigenesis. The expression of Nectin-4, the receptor of measles virus, in some mammary tumor cells may provide a model to study the oncolytic virotherapy of breast cancer. The manuscript is overall well written. Following a few correction/modification may improve the manuscript.

1. Typo: “Nectin-4 has been also been reported” (page 11) should be corrected.

2. Figures 5 and 6 can be combined to save space.

3. Please provide a little bit more information in the Figure legend of Figure 1.

Reviewer #3: This interesting paper highlights pathological characteristics of another animal model of breast cancer, the tree shrew. While the pathological descriptions are evident, the manuscript does focus quite a bit on the familial inheritance of mammary tumors seen in their model. However the data supporting these observations is quite minimal aside from pedigree charting. Are these familial patterns driven by germline mutations that can be identified,particularly those associated with inherited forms of breast cancer. I think the genetic aspects should be explored more here for discussion, including sequencing of at least the major inherited drivers in breast cancer.

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Reviewer #1: No

Reviewer #2: No

Reviewer #3: No

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Pathological and genetic aspects of spontaneous mammary gland tumor in Tupaia belangeri (Tree shrew)

PONE-D-20-04206R1

Dear Dr. Tsukiyama-Kohara,

We are pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it complies with all outstanding technical requirements.

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With kind regards,

Yi Li, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments: