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1 Author's response to reviews Title:microRNA alterations in mammary epithelial stem cells: a crucial contributing factor towards breast cancer risk reduction in case of early pregnancy Authors: Sushmita Nandy (sushmita.nandy@ttuhsc.edu) Ramadevi Subramani (ramadevi.subramani@ttuhsc.edu) Venkatesh Rajamanickam (venkateshr89@gmail.com) Rebecca Lopez (rebecca.lopez@ttuhsc.edu) Arunkumar Arumugam (arunkumar.arumugam@ttuhsc.edu) Thiyagarajan Boopalan (thiyagarajan.boopalan@ttuhsc.edu) Rajkumar Lakshmanaswamy (rajkumar.lakshmanaswamy@ttuhsc.edu) Version:2Date:21 May 2014 Author's response to reviews: see over

2 Dear Editor, Thank you for considering our manuscript for publication in your journal. Below we have addressed all the concerns raised by the reviewers point by point. 1. In order to analyze the mammary microrna composition in rats after a full pregnancy the authors had removed the pups immediately after delivery. By doing so, the authors induced involution and did not allow the rats to go through a normal lactation round. I believe that this issue needs to be addressed. We and others in our previous experiments have observed no differences in the mammary glands of animals that lactated compared with the ones that did not lactate. The changes in the mammary gland morphology were very similar irrespective of forced involution or natural involution. In addition, an earlier study showed that unilaterally thelectomized glands at parturition had no effect on the localization of either adenocarcinomas or benign mammary tumors (Moore BP et al, 1981). Based on these findings we believe that removing the pups immediately after delivery would not have affected the results of our experiments. 2. It has been shown in the past that the mammary stem cell composition can be altered during the estrous cycle. Therefore, it is essential to determine the estrous cycle status of those rats before drawing conclusions regarding the mammary gland composition. We agree that there are changes in the mammary gland stem cell composition during the estrus cycle of the rodents. But for this study, we performed vaginal smears and collected tissues from animals in their diestrus phase of the estrus cycle. This phase was selected as it has been shown that rat mammary epithelium had the highest proliferation during diestrus phase (Schedin P et al, 2000). 3. The author s claim that some of the differential regulated genes are involved in cell cycle (inhibitory activity at the G1-S phase of the cell cycle). This point can be addressed by performing experiments which address the cell cycle/proliferation, like BrdU-assays (in vivo or in vitro). This information will strengthen the conclusions of this manuscript,

3 especially since the authors did not observe any changes in either the stem cell number by FACS (data are not shown and I would like to know whether the authors tried any other FACS approaches to prove their point) or in the colony formation capacity of these cells. It is my personal belief that proving this point will make this manuscript much stronger. As per the reviewer s recommendation, an EdU based proliferation assay was performed in mammary epithelial derived stem cells from both nulliparous and parous groups. The results have been included in the manuscript as Supplementary Fig. 1. The method and legend for the same has been incorporated under the Methods (Page No: 8; line: ) and Legends (Page No: 25; line: ) section. The findings of this assay demonstrate higher cycling rate of virgin EpSCs compared to parous, which has been incorporated in the Results (Page No. 10; line ) section. Sphere forming efficiency of these cells was determined and the data has been shown in Fig 1C. No other FACs based assay was performed. 4. In line 119 the author claims In this study, we demonstrate that pregnancy alters molecular processes in mammary EpSCs, leading to a decreased risk of mammary cancer. This statement is incorrect since: a. The authors did not define any differences in the mammary stem cells nor, to my understanding, tried to achieve a deeper insight into the mammary epithelial stem cells (ALDH positive cells is not enough to determine a cell as a stem cell). For example, Sharma et al., 2011, are using in their publication an additional way of analyzing the rat mammary gland (D. Sharma, B.M. Smits, M.R. Eichelberg, A.L. Meilahn, M.J. Muelbl, J.D. Haag, M.N. Gould: Quantification of epithelial cell differentiation in mammary glands and carcinomas from DMBA- and MNU-exposed rats. PLoS One, 6 (2011), p. e26145). We in this paper have tried to show the molecular differences in the virgin and parous mammary epithelial stem cells at the transcriptional and translational levels. We agree that markers other than ALDH have been used by different groups to identify and study stem cells including CD44 + /CD24 -/low and CD49f + /Epcam - to mention a few. However, ALDH as a marker to enrich

4 stem cell population from the epithelial cells of the mammary gland has been used earlier (Ginestier C et al, 2007; Ingrid Ibarra et al, 2007). The aim of the authors in the quoted paper was to characterize the rat mammary epithelial cells for various cell surface proteins to analyze the differences due to the mammary gland differentiation and carcinogenic insult. b. Other than a speculation regarding the outcome of the pregnancy, no evidence are given to support this statement (those rats did not complete a normal lactation round, when the literature refers to cancer risk and pregnancy in humans, nursing the newborn is considered). Therefore, I think the authors should reconsider this statement. We agree with the reviewer s comment lactation could have an impact on breast cancer risk. It has been time and again shown that timing of pregnancy is the most critical factor in decreasing the risk of breast cancer while 12 months of lactation offers a minimal level of risk reduction against breast cancer. A large meta-analysis data clearly demonstrated that the first pregnancy confers approximately 50% decrease in risk of breast cancer and each additional pregnancy confers another approximately 7% decrease in risk of breast cancer. Twelve months of lactation lead to only about 4% decrease in the risk of breast cancer (Collaborative group on Hormonal Factors in Breast Cancer, 2002). Considering these facts the influence of lactation on breast cancer risk is relative minimal. Additional comments: Figure 1: The authors used IF to establish the presence of stem cells in mammospheres, what is the N-number for those experiments. How many mammospheres were analyzed (n=?) Additional statistical information will be appreciated. n=6. The information has been incorporated in the manuscript under the legends section (Page No: 22; line: 500). SOX2 and OCT4 positive cells were observed in all the experimental sets. This was a qualitative analysis and thus no statistics were applied. Figure 2: Based on the volcano plot in figure 2c and 2d the number of genes which are up or down regulated is not very high, therefore it will be better to present the information in

5 a table, which will include all of the gene information, as well as the statistical information (p-value). We already had the list of the differentially regulated genes tabulated in Table 1 and 2. The p- values for each of the genes have been included in Table 1 (Page No: 26) and 2 (Page No: 27). Figure 3: The statistical information is missing. What is the N-number how many times were these experiments repeated?, all this information should be presented in the figure or at least in the figure legend. n=6. The information has been incorporated in the manuscript under the legends section (Page No: 23; line: 528) Figure 4: How many times was the western blot performed? There s no statistical information in figure 4 a b and c. The western blots were repeated atleast thrice for every protein and the standard error has been incorporated in Fig 4a, b and c. Necessary information regarding this has been included in the manuscript under the legends section (Page No:24; line:542) Reviewer's report: Nandy et al., in this manuscript investigates molecular causes of increased breast cancer risk in nulliparous women compared to parous women using mammary glands of post-partum animals and virgin animals. Undoubtedly it is an important area of research in breast cancer etiology to understand the parity related protection from breast cancer and most importantly authors tackled a challenging area to investigate transcriptomic differences in mammary stem cell populations isolated from parous and nulliparous animals. Authors' study revealed some interesting and meaningful results such as up regulation of p21 which is regulated by micrornas mir-28, mir- 125a and mir-503 as well as down regulation of EMT related genes such as Zeb, Vimentin, N- cadherin etc. However, I believe authors have not provided adequate molecular explanation for the down regulation of these genes. Down regulation of the following micrornas such as let-7, mir-93, mir-125 and some others in parous mammary gland compared to that of the virgin animals show an apparent conflict with the previously published literature Xhong et al 2010, Yu et al 2007, Iliopoulos et al., 2009, Li et al 2012). These studies directly linked down regulation of

6 these mirnas to stemness of breast cancer and EMT, however authors concluded that downregulation of these mirnas resulted in up regulation of PPARgamma in mammary glands of parous animals. First landmark paper on let-7 by Yu et al., in 2007 suggested that let-7 targeted H-Ras and HMGA2 while H-ras controlled self-renewal latter controlled differentiation. In my opinion, authors need to reconcile their findings and examine if there are indeed changes in the HMGA expression which regulate differentiation. We believe that micrornas function in a context dependent manner. The current data is based on the mammary epithelial stem cell differences as a result of parity. And it needs to be noted that these are normal stem cells which are not yet apparently transformed. The experiments performed in the articles by Yu, F; 2007 and Iliopoulos et al., 2009 involves breast cancer cells or cell lines (transformed or non-transformed). The article by Li X, 2012 talks about lin28/let-7 in terms of hematopoiesis. The article by Xhong, 2010 definitely talks about mammary epithelial stem cells derived from virgin mice and the levels of Lin28 and let-7 compared to its treatment with carcinogen. We speculate that the conflict in ours and other s findings may be attributed to the difference in the context of experimentation. Level of interest: An article of importance in its field Quality of written English: Acceptable Statistical review: Yes, and I have assessed the statistics in my report. Declaration of competing interests: I declare that I have no competing interests

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