Expression of Concern (20 ^th October 2023): We, the Publisher and Editor of F1000Research, are issuing an Expression of Concern for the following article:

A. Abd M, A. Abbas S and G. Shareef L. Impact of serum leptin and adiponectin levels on breast cancer in postmenopausal Iraqi women: an observational Study [version 1; peer review: awaiting peer review]. F1000Research 2022, 11:1572 ( https://doi.org/10.12688/f1000research.127528.1).

After publication of this article, questions about the integrity of the ethical approval were brought to the attention of the F1000 Editorial Team. We have reached out to the authors requesting that they respond to the concerns raised and provide additional information to support the integrity of the content. However, despite multiple attempts to contact the authors, and their institution, they have not responded to our queries within the requested timeframe. Therefore, as we continue to work through the issues raised, we advise readers to interpret the information presented in the article with due caution. The authors have been sent notification about this Expression of Concern.

Editorial Note (13 ^th July 2023): Since publication, concerns have been raised to the Editorial Team regarding the ethical approval for this study, as well as overlap in the sample and methods to other papers by these authors. The Editorial Team requested explanations regarding the similarities on 19 ^th May and 6 ^th June 2023, and the institution was contacted on 21 ^st March, 6 ^th April and 25 ^th April 2023 to verify the ethical approval. Neither the author nor institution have provided responses to our requests. The Editorial Team will update this Editorial Note as the situation progresses. Peer review activity has been suspended for this article until we receive an explanation from the authors/institution.

According to GLOBOCAN 2020 statistics, breast cancer is one of the most prevalent malignancies diagnosed today and the fifth most prominent cause of cancer-related deaths, with around 2.3 million new cases diagnosed globally. ¹ According to the Iraqi Cancer Registry report of 2020, breast cancer is the most prevalent malignant tumor, with an incidence rate of about 19%. ² Additionally, breast cancer is regarded as the second-leading cause of death from malignancy in the entire Iraqi population, with an incidence rate of roughly 13%, and the first leading cause of death from malignancy in Iraqi women, with a rate of incidence of 25%. ² World Health Organization classified obesity as a serious world-wide medical issue, ³ affecting a large proportion of the population and correlating with many chronic conditions, such as diabetes mellitus, cardiovascular disease, hypertension, as well as certain types of cancer, ⁴ which all can cause a significant burden on the medical systems of the countries worldwide, ⁵ the connection with breast cancer is substantial. ⁶ Adipose tissue is considered not only a reservoir for the storage of lipids but also an endocrine gland with a significant role in the regulation of the body's metabolism and the different immune responses, which can, in turn, affect the metabolism of other cells and enzymes which in turn affect the steroid hormone metabolism. ⁷ White adipose tissue secretes adipokines, which have a wide range of effects on various biological processes, including inflammation, insulin signaling, glucose metabolism, and lipid metabolism. ⁸ Adiponectin or adipocyte complement-related protein is a monomer of 30 kDa that circulates in the plasma as low- and high-molecular-weight multimers. ⁹

Leptin, encoded by the obese (Ob) gene, is a multifunctional polypeptidic protein (16 kDa). Its production and the levels of plasma rise in proportion to fat accumulation. ^{10 , 11} Leptin can influence a diverse range of biological processes. This includes breast tumorigenesis in addition to its neuroendocrine function. This adipokine can affect the biology of breast cancer in endocrine, paracrine, and autocrine, and this has been amply demonstrated. ¹² Distant and local adipocytes primarily produce it, but it is also produced by the cells of the epithelial tumor as well as by other stromal cells in the tumor (cancer-associated fibroblasts), numerous intracellular downstream signaling pathways, including the JAK2/STAT3, MAPK, and PI3K/Akt pathways, which are involved in the regulation of cell proliferation, differentiation, survival, migration, and invasion, are activated as a result of leptin binding to the long ObR isoform. ^{13 , 14} White adipocyte hypertrophy and hyperplasia limit their vascularization, lowering oxygen availability. Due to the hypoxic state, there is increased oxidative stress, insulin resistance, ischemia, adipocyte necrosis, and the release of inflammatory and angiogenic proteins. ¹⁵ Adipose tissue dysfunction in obesity is associated with an aberrant mediator release profile that results in a chronic inflammatory state. Adiponectin is downregulated due to an increase in leptin and pro-inflammatory cytokines; as a result, anti-inflammatory and anti-tumor actions are reduced. ¹⁶

The objective of this study was to compare the levels of serum adiponectin and leptin in postmenopausal breast cancer patients who had obesity or were not obese, to a non-obese control group, to discover possible correlations between these biomarkers and the development of breast cancer.

The study recruited 90 participants as shown in Figure 1. The studied groups demonstrated non-significant differences in median (IQR) of age or height, including the three studied groups, as shown in Table 2. ¹⁷ In addition, group 3 (control participants without breast cancer or obesity) showed higher serum adiponectin levels than both group 1 (participants with breast cancer and obesity) and group 2 (participants with breast cancer without obesity), while no significant difference in serum adiponectin levels was showed between group 1 and group 2, as shown in Table 3 and Figure 2.

Group 1 (participants with breast cancer and obesity) showed a higher Serum Leptin level than both group 2 (participants with breast cancer without obesity) and group 3 (control participants without breast cancer or obesity). In contrast, no significant difference in serum leptin levels was shown between group 2 and group 3, as shown in Table 3 and Figure 3.

This study found a moderate negative correlation between BMI and adiponectin, while a robust positive correlation between leptin and BMI was found. The study also found the correlation between serum adiponectin and leptin levels was moderately negative, as shown in Table 4.

From this study, the levels of serum adiponectin showed significantly higher values in the control group (group 3) when compared to both groups 1 (participants with breast cancer and obesity) and group 2 (participants with breast cancer without obesity), as shown in Table 3. This may be due to central adiposity and the negative association with body mass index. ¹⁸ In addition, the down-regulation of the receptors, AdipoR1, and AdipoR2, plays a crucial role in the low adiponectin levels in individuals with obesity. ¹⁹ Along with the previously listed factors, obesity is a chronic state of inflammation defined by high inflammatory cytokines levels, including IL-6, IL-8, TNF-, and others. ^{20 , 21} These cytokines inhibit adiponectin transcription, resulting in low levels of adiponectin. ²² This study agreed with many previous studies, where Kredy et al.; and Miyoshi et al.; found that patients with breast cancer had lower serum adiponectin levels than the healthy control subjects. ^{23 , 24} At the same time, it disagreed with the study by Shafika et al., who found that serum adiponectin levels in breast cancer patients were higher than in the control group. ²⁵

In this study, participants with breast cancer and obesity (group 1) showed significantly higher serum leptin levels compared to non-obese breast cancer (group 2) and non-obese control (group 3). This result may be explained by the high quantity of leptin expressed at the gene level in adipose tissue in people with obesity. ²⁶ Furthermore, there are significant positive relationships between plasma leptin levels and body fat percentage. ²⁷ And this agreed with the finding of a study by Zeinab et al. which illustrated that breast cancer patients had significantly higher serum leptin levels than healthy controls. ²⁸ The result of this study also agreed with other studies which also compared patients with breast cancer and a healthy control group with the insignificant difference in BMI between the two groups; where Manar et al. and Adel et al.; found that the levels of serum leptin higher in patients having breast cancer compared to healthy controls. ^{29 , 30} In this study, both group 2 (non-obese breast cancer) and group 3 (non-obese control) patients showed no significant difference in serum leptin levels, since leptin levels in the body are directly related to BMI, and both of these groups have nearly the same BMI, and this finding agreed with by study done by Marc et al.; who showed the same finding in their study. ³¹ In this study, BMI showed a significantly robust positive correlation with leptin (ƿ = 0.922), as leptin levels directly relate to body fat percentage. ^{32 , 33} On the other hand, BMI showed a significant moderate negative correlation with adiponectin (ƿ = -0.306) since the adiponectin levels have an inverse relation with body fat content. ⁹ While the Spearman correlation test showed a significantly moderate weak correlation (ƿ = -0.352) between leptin and adiponectin, this may be explained by continuous inflammatory status in obesity, which leads to altered transcription of adiponectin due to high levels of leptin in the state of obesity. ²²

Women with obesity and breast cancer were found to have low serum levels of adiponectin, which reduces the protective actions of adiponectin and may promote the growth of breast cancer. On the other hand, leptin levels were higher in the serum of women with obesity and breast cancer than in women who were not obese, which may be due to leptin's pro-inflammatory activities in addition to other variables.