Potential Role of CCN Proteins in Breast Cancer: Therapeutic Advances and Perspectives

Round 1

Reviewer 1 Report

Dear Authors,

 

I have reviewed the manuscript „Potential role of CCN proteins on breast cancer: Therapeutic advances and perspectives”.

My comments:

1. Row 46. CT module – the abbreviations should be explained at the first presentation.
2. Row 50. ductal carcinoma is not a distinct entity anymore. I advised using the WHO classification. Instead of ductal carcinoma the term invasive carcinoma not otherwise specified (NOS)
3. Row 186. „CCN1 in breast cancer cells results in an increase in tumor size” I would advise using the „associated with” term for this observation.
4. Row 324. EGCG inhibits TNBC progression. I think it is important to emphasize that this is an in vitro observation.
5. Row 240. My advice for this sentence: “Overexpression of the 240 CCN protein may contribute to the aggressive behavior of breast cancer with osteolytic bone metastases by increasing nuclear 241 translocation of nuclear factor of activated T cells c1 (NFATc1) and calcium oscilla-242 tions[14].”

 

With these modifications, my opinion is that this manuscript is worth publishing.

 

 

Author Response

I have reviewed the manuscript „Potential role of CCN proteins on breast cancer: Therapeutic advances and perspectives”.

Critical comment

1. Row 46. CT module – the abbreviations should be explained at the first presentation.

Response>Thank you for your suggestion. We have added the abbreviations at line 46.

2. Row 50. ductal carcinoma is not a distinct entity anymore. I advised using the WHO classification. Instead of ductal carcinoma the term invasive carcinoma not otherwise specified (NOS)

Response> We have removed the ambiguous information of “ductal carcinoma” altogether.

3. Row 186. „CCN1 in breast cancer cells results in an increase in tumor size” I would advise using the „associated with” term for this observation.

Response>We have changed the statement accordingly which is available at line 178.

4. Row 324. EGCG inhibits TNBC progression. I think it is important to emphasize that this is an in vitro observation.

Response> We have emphasized the “in vitro study” now available at line 323.

5. Row 240. My advice for this sentence: “Overexpression of the 240 CCN protein may contribute to the aggressive behavior of breast cancer with osteolytic bone metastases by increasing nuclear 241 translocation of nuclear factor of activated T cells c1 (NFATc1) and calcium oscilla-242 tions[14].”

Response> We have made change accordingly at line 233.

 

With these modifications, my opinion is that this manuscript is worth publishing.

Response> We appreciate your support and valuable comments. It has been helpful in many ways to improve our study. We have enclosed the point-by-point response of your comments.

Reviewer 2 Report

This is a very holistic review on the role of CCN proteins in Breast cancer. Though some modifications are needed to be done:

1. The English is not yet perfect. There are grammar and sentence structure needed to be improved. e.g in title, in breast cancer is more appropriate than on breast cancer. Line 21: which are exist should be which exist. Line 34: carcinoma on focus is not fitting. Line 87: there should not be bracket after including, etc...

2. In table 1, the role of different CCNs in survival in breast cancer if known can also be added.

3. There are now reports and also based on in-silico databases, there are microRNAs regulating CCNs. More elaboration in this regard will be useful and if possible, a table showing microRNAs regulation CCNs in breast cancer will be helpful. 

Author Response

This is a very holistic review on the role of CCN proteins in Breast cancer. Though some modifications are needed to be done:

Response> We appreciate your support and valuable comments. It has been helpful in many ways to improve our study. We have enclosed the point-by-point response of your comments as below.

1. The English is not yet perfect. There are grammar and sentence structure needed to be improved. e.g in title, in breast cancer is more appropriate than on breast cancer. Line 21: which are exist should be which exist. Line 34: carcinoma on focus is not fitting. Line 87: there should not be bracket after including, etc...

Response> Thank you for your suggestion. We have made minor changes at line 22, line 87, line 90, line 92, line 99,line 103, line 105, line 117, line 118, line 121, line 148, line 170, line 173, line 178, line 233, line 274, line 280, line 285, line 300, line 301, line 323, line 324, line 337, line 341, line 396, line 415, line 419 to remove grammatical error. We have removed line 87, 99, 112, 114.

2. In table 1, the role of different proteins in survival in breast cancer if known can also be added.

Response> The role of different proteins in survival in breast cancer has been added at line 157 as below: CCN1, CCN3, CCN5, CCN6 plays critical role in survival in breast cancer.

3. There are now reports and also based on in-silico databases, there are microRNAs regulating CCNs. More elaboration in this regard will be useful and if possible, a table showing microRNAs regulation CCNs in breast cancer will be helpful. 

Response>Thank you for your suggestion. We have added the paragraph of MicroRNA regulation of CCN genes in breast cancer at line 288 as below.

MicroRNA regulation of CCN gene in breast cancer

MicroRNA, commonly referred as miRNA, are small noncoding RNA molecules of ~25 nucleotides which can regulate gene expression by binding with 3’ untranslated region of mRNA [1]. MiRNA has emerged as a potential regulator of all the aspects of breast cancer [2].

Gene	MicroRNA		Role in breast cancer
CCN3	miR- 30c [3]	“complete” expression can inihibit breast cancer progression [4] whereas, overexpression leads to aggressive behavior of the cancer [5]
CCN2	miR-124–3p, miR-18a-5p, miR-145–5p[1]	Can cause migration and angiogenesis of breast cancer cells [6]

Table 1: MicroRNA involved in regulation of CCN gene expression.

1. Petri, B.J., Regulation of breast cancer metastasis signaling by miRNAs, C.M. Klinge, Editor. 2020. p. 837–886.
2. O'Connor, L.M., et al., miRNA Dysregulation in Breast Cancer. 2013.
3. R., D.J., et al., hsa-mir-30c promotes the invasive phenotype of metastatic breast cancer cells by targeting NOV/CCN3. Cancer cell international, 2014. 14.
4. Sherbet, G., Metastasis promoter S100A4 is a potential molecular therapeutic target. Cancer genomics & proteomics, 2006. 3(3-4): p. 203-216.
5. Ouellet, V., et al., CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone. Am J Pathol, 2011. 178(5): p. 2377-88.
6. Chien, W., et al., Expression of connective tissue growth factor (CTGF/CCN2) in breast cancer cells is associated with increased migration and angiogenesis. Int J Oncol, 2011. 38(6): p. 1741-7.

This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.

Round 1

Reviewer 1 Report

I have reviewed the manuscript „Potential role of CCN proteins on breast cancer: Therapeutic advances and perspectives”.

The regulation processes which take part in breast cancer formation and progression are of utmost importance. The knowledge of the key regulatory processes gives us the opportunity to better understand the disease and find new medicines against it. This manuscript aimed to collect knowledge about CCN matricellular proteins in breast cancer.

With the 73 references, it accumulates a considerable amount of data and gives an insight into the function of the CCN molecules.

In advance, I have to tell you that I am a clinician and I see the data from a practical point of view. In this regard, it has not become clear which CCN molecule could be a good target in breast cancer treatment. As the authors stated in the conclusion „a single member of the CCN family can be oncogenic or tumor suppressive depending on the nature of the breast cancer”. In the text, they use the indicative „paradox” and „ambiguous”, too. In rows 182 and 200, it is stated that the CCN1 enhances and inhibits tumor formation. In my opinion, it should be made more clear which molecule is a potential target of therapy.

My critical comments:

1. In the abstract the sentence „… has been implicated in both cure and disease with impacts on interaction” may have to be restructured (disease evolution?)
2. Row 50. ductal carcinoma is not a distinct entity anymore.
3. Row 51. „not defined as breast cancer”. The malignant phylloid tumor is a good example of breast soft tissue sarcoma.
4. Row 304. „Dexamethasone …is widely used to treat breast cancer”. It is not true. We use it as a premedication to prevent chemotherapy induces nausea and vomiting.
5. There are some data for which reference seems to be needed:

row 71,

row 96,

row 160 (for CCN2 overexpression and also for estrogen-inducible),

for Table 1

row 304-305.

6. row 344. prevention or treatment?
7. row 299. „ZOL, DEX play vital roles in inhibiting breast tumor formation, proliferation and metastasis” suggests that these agents are basic constitutes of breast cancer therapy. I advise to remove „vital”.
8. There are some references that are not connected to breast cancer which should be marked also in the text (row 46/ref 29, row 185/ref 36, row 320/ref 60.
9. row 215. „fibroblasts of breast tumor cells” should be rephrased.
10. row 238-240. the sentence should be rephrased.

11. The authors called their work „a study” (row 33). In the method section, a more detailed description of the study should be presented.

Reviewer 2 Report

Please find below my evaluation of the manuscript AHMED et al Curr.Oncol 2021 entitled Potential Role of CCN Proteins on Breast Cancer : Therapeutic Advances and Perspectives
 
My conclusion is that the manuscript is not acceptable for publication as it stands.
The level of science and the manuscript organization are very poor.
Sadly, all along their manuscript the authors use a vocabulary that is not scientific at all, full of approximation and errors that render the lecture of the text extremely exhausting.
The reviewer cannot spend hours correcting the flawed affirmations of the authors.
This manuscript does not bring anything new, as compared to two recent reviews already published on the exact same subject in the few past months in other journals .
Submitting a manuscript for publication in a scientific journal needs an extensive level of carefullness that is obviously not achieved here.
The referencing is extremely bad and neither up to date, nor menionning the original manuscripts that are still considered as fundamentals although they were written many years ago…The CCN field was not born in the last decade !
Several prominent and sound manuscripts reporting the existence of a family of CCN proteins and predicting their complex mode of action in the regulation of extracellular signaling were published, soon after the discovery of CCN1,2, and 3 between 1991 and 2005 …and should still be cited.
Last but not least, the text appears as the juxtaposition of several paragraphs, a patchwork of paragraphs, written by different co-authors who seem to ignore what the others wrote in the same manuscript…
No unity in the reasoning, nor in the presentation, with several assertions contradicting others.
It is a matter of respect for the reviewers and the potential readership.
 
 
A few examples of carelessness:
 
1) from the very beginning of the article, the abstract contains inconstancies and mistakes.
 
Among them :
Lines 20: “six separate members in mammals” : incorrect. The situation is not restricted to mammals.
 
Line 21 “four distinct motifs” . Not correct one cannot mix the notion of motifs and modules. Quite different.
 
-line 22  “ by binding to integrin receptors” incorrect
 
Line 23 “ by a typical expression of CCNs” meaningless
 
Line 29 “pro tumorigenic CCN3” incorrect
 
Line 32 “ tumor inhibition and tumor supression of CCN3” this is in contradiction with line 29
 
Last two sentences from line 34 are “full of emptiness”
 
INTRODUCTION
 
Line 47 “They share …exception” this sentence is meaningless and wrong. The CCN proteins do not share “a conserved motif” but 4, one in each of the four modules…
Line 58 : the sole association of proliferation and migration to tumoriginic and metastatic potentials is a rather obsolete idea. Some CCN proteins that inhibit cell proliferation show both a high tumoregenic and metastatic potentials.
Line 60 “anti proliferative role where their expression can inhibit breast cancer growth” incorrect and contradictory to what has been writing above in the manuscript.
 
Lines 63 to 66: example of a sentence devoided of any scientific meaning and support.
 
A word on the nomenclature. Line 72 …
There is a HUGO committee validated nomenclature which is the only official one to be used.
The authors of this review should carefully consider this point
 
Line 76 “has IGF-binding ability”  Not true. The construction of a recombinant CCN protein carrying the IGFBP module of an IGFBP protein could not bind IGF…
 
Line 77 “followed by an N-terminal signal peptide “ This is false.
 
Line 81 : “reciprocally” is not the proper word to be used.
 
Line 86 “especially with Notch1 and cell surface integrins” too limitative, hence not scientifically acceptable.
 
Line 90 reference 10 is not the one to be used for the description of the CCN family.