Breast Precancerous Lesions Research Articles

IJCM_229A: A Community-based screening programme for oral, breast, and cervical cancer in the rural area of Dakshin Kannada

Background: Karnataka recorded 87304 new cancer cases in the year 2021. Breast, lip and oral cavity, cervix were the top cancer sites amongst all sexes and are preventable. Despite the nation-wide launch of Population-based screening (PBS) in 2016, the reported coverage of individuals who were screened for these three cancers in Dakshin Kannada was 0.4% (NFHS-5). The study introduces on-site screening for oral and breast cancer in the community. Objectives: To estimate the proportion of pre-cancerous lesions of oral, breast, and cervical cancer, through community-based screening in adults aged 18 to 65 years, in the catchment area of a medical college in Dakshina Kannada Methodology: This observational study was conducted among all persons aged 18 to 65years, residing in the rural catchment area of a medical college in Mangalore taluk of Dakshina Kannada and consenting for the study. Pregnant women and persons with prior diagnosis of oral, breast or cervical cancer were excluded. Two-stage cluster sampling was used to enrol an estimated sample of 1120 beneficiaries. The study comprised of house-to-house survey, cancer awareness sessions, and community-based screening. Screening tests included Oral visual examination, clinical breast examination, iBreast examination (iBE; electronic palpation by ibreast device), and Pap smear tests. Participants who screened positive were referred for diagnostic tests and management. Results: The study was completed with survey of 556 households, 3 cancer awareness sessions, and screening of 525 beneficiaries (325 females and 200 males) for oral, breast, and cervical cancer. Three participants screened positive for oral cancer, and one participant for breast cancer, who were referred for management to tertiary care hospital attached to the medical college. 25% of female participants underwent cervical cancer screening, with no one detected with pre-cancerous lesions. Conclusion: A combination of house-to-house and camp-based approaches along with awareness sessions results in improved coverage of PBS in the community.

Effect and mechanism of Xihuang Pills on rats with precancerous lesions of breast

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.

Kaempferol induces mitochondrial dysfunction and mitophagy by activating the LKB1/AMPK/MFF pathway in breast precancerous lesions.

Kaempferol has been suggested to be an effective anticancer agent in several malignant tumors. However, its function and mechanisms in breast precancerous lesions remain largely elusive. Here, we showed that kaempferol induced excessive mitochondrial fission and mitochondrial damage with activated mitochondrial fission factor (MFF)-mediated dynamin-related protein (DRP) 1 mitochondrial translocation. As a result, the PTEN-induced putative kinase 1 (PINK1)/Parkin signaling pathway was activated, accompanied by excessive mitophagy and reduced mitochondrial mass in cells. We also revealed that kaempferol-induced lethal mitophagy contributed to inhibiting breast precancerous lesion growth in vitro and in vivo. Furthermore, we verified serine/threonine kinase 11 (STK11/LKB1)/AMP-activated protein kinase (AMPK) pathway deficiency in breast precancerous lesions. Moreover, LKB1/AMPK pathway reactivation by kaempferol was required for excessive mitochondrial fission and lethal mitophagy. Taken together, our findings shed new light on the molecular mechanisms related to breast cancer prevention by kaempferol and provide evidence for its potential clinical application.

Comparison of in vivo plasma pharmacokinetics and urine excretion of main components in Xihuang Formula in rats with precancerous lesions of breast cancer

The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and β-boswellic acid(β-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and β-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and β-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of β-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of β-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of β-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of β-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of β-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.

Immunoprofiling of BRAFV600E in Precancerous and Cancerous Lesions of Breast by Immunohistochemistry and its Association with Clinicopathological Features

Introduction: Breast carcinoma in women is one of the few causes of morbidity and mortality which concerns the health providers. The molecular basis of breast carcinoma in recent years has provided the insight for the genesis of carcinoma, the prognostic, and predictive utility for targeted therapies. Aim: A study has been planned with the aim to know immunoprofiling of BRAFV600E in precancerous and cancerous lesions of the breast by Immunohistochemistry (IHC) and its association with clinicopathological features. Materials and Methods: The subjects will be divided in two groups of 45 cases each: Precancerous breast lesions; and Invasive ductal carcinoma. The tissue of these cases will undergo IHC of BRAFV600E. The comparison of expression is to be brought out and the clinicopathological association of immunoexpression of BRAFV600E will also be studied.

Abstract P007: Short-term PI3K inhibition prevents breast cancer in preclinical models

Abstract Antiestrogen medication is the only chemoprevention currently available for women at a high risk of developing breast cancer; however, antiestrogen therapy requires years to achieve efficacy and has adverse side effects. Therefore, it is important to develop an efficacious chemoprevention strategy that requires only a short course of treatment. PIK3CA is commonly activated in breast atypical hyperplasia, the known precancerous precursor of breast cancer. Targeting PI3K signaling in these precancerous lesions may offer a new strategy for chemoprevention. Here, we first established a mouse model that mimics the progression from precancerous lesions to breast cancer. Next, we demonstrated that a short course prophylactic treatment with the clinically approved PI3K inhibitor alpelisib slowed early lesion expansion and prevented cancer formation in this model. Furthermore, we showed that alpelisib suppressed ex vivo expansion of patient-derived atypical hyperplasia. Together, these data indicate that the progression of breast precancerous lesions heavily depends on the PI3K signaling, and that prophylactic targeting of PI3K activity can prevent breast cancer. Citation Format: Amy T. Ku, Adelaide Young, Ahmed A. Ibrahim, Wen Bu, Weiyu Jiang, Meng Lin, Laterrica C. Williams, Bryant McCue, George Miles, Chandandeep Nagi, Fariba Behbod, Yi Li. Short-term PI3K inhibition prevents breast cancer in preclinical models. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P007.

Short-term PI3K Inhibition Prevents Breast Cancer in Preclinical Models.

PI3K protein is abnormally high in breast precancerous lesions. This preclinical study demonstrates that the FDA-approved anti-PI3K inhibitor alpelisib can prevent breast cancer and thus warrant future clinical trials in high-risk women.

β-Boswellic Acid Suppresses Breast Precancerous Lesions via GLUT1 Targeting-Mediated Glycolysis Inhibition and AMPK Pathway Activation.

Breast carcinoma is a multistep progressive disease. Precancerous prevention seems to be crucial. β-Boswellic acid (β-BA), the main component of the folk medicine Boswellia serrata (B. serrata), has been reported to be effective in various diseases including tumors. In this work, we demonstrated that β-BA could inhibit breast precancerous lesions in rat disease models. Consistently, β-BA could suppress proliferation and induce apoptosis on MCF-10AT without significantly influencing MCF-10A. Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis suggested that β-BA may interfere with the metabolic pathway. Metabolism-related assays showed that β-BA suppressed glycolysis and reduced ATP production, which then activated the AMPK pathway and inhibited the mTOR pathway to limit MCF-10AT proliferation. Further molecular docking analysis suggested that GLUT1 might be the target of β-BA. Forced expression of GLUT1 could rescue the glycolysis suppression and survival limitation induced by β-BA on MCF-10AT. Taken together, β-BA could relieve precancerous lesions in vivo and in vitro through GLUT1 targeting-induced glycolysis suppression and AMPK/mTOR pathway alterations. Here, we offered a molecular basis for β-BA to be developed as a promising drug candidate for the prevention of breast precancerous lesions.

The role of microductectomy in the diagnosis and treatment in women with pathologic nipple discharge

Objectives: Approximately one tenth of the patients who apply to the breast polyclinics complain of nipple discharge. Apart from pregnancy and lactation, spontaneous, unilateral, bloody or serous discharge originating from a single duct describes the Pathological Nipple Discharge (PND). The aim of this study is to show that precancerous breast lesions, which can be easily overlooked by conventional diagnostic methods, are detected with the microductectomy performed with the correct indication and it is possible to complete the appropriate treatment. Methods: Fifty-five microductectomy procedures were performed in 55 female patients who applied to the relevant clinic with the complaint of nipple discharge between January 2013 and August 2018 and who met at least two of the three criteria of pathological nipple discharge (spontaneous, single ductus, bloody or serous) except pregnancy and lactation. Prospectively collected information was evaluated retrospectively. Results: The average age of the patients in the study ranged from 23 to 73 years (mean age 45.5 years, median age 47 years). Out of 55 procedures, 28 (50.9%) were performed in women of reproductive age, 27 (49.1%) were performed in women in menopause. The discharge was localized to the right breast in 28 patients, and to the left breast in 27 patients. Forty-one of the 55 patients included in the study met all of the criteria for pathological nipple discharge, while the other 14 patients had at least two of the three criteria. Final pathologies were classified as follows; intraductal papilloma / papillomatosis with atypia, intraductal papillary carcinoma (IPC) and ductal carcinoma in situ (DCIS); Potential Neoplastic and Malignant Lesion (PNML). Conclusions: In cases where direct intraductal imaging methods cannot be applied in patients admitted to the polyclinic with pathological nipple discharge, microductectomy emerges as an effective diagnosis and treatment method that can be applied with low morbidity.

The Chinese Herbal Formula Ruyan Neixiao Cream Inhibits Angiogenesis of Precancerous Breast Lesions via Regulation of Ras/Raf/MEK/ERK Signaling Pathway.

Ruyan Neixiao Cream (RUc) is a traditional Chinese herbal formula which can effectively inhibit the angiogenesis of breast precancerous lesions. In order to reveal the specific mechanism, we carried out experiments in vitro and in vivo. We found that the conditioned medium of MCF-10AT cells treated with RUc transdermal solution (RUt) could significantly inhibit the proliferation, migration, invasion, tube formation of HUVECs and the capillary formation of rat aortic rings. RUt may down-regulate the expression of VEGF, MMP2, and MMP9 in MCF-10AT medium by down-regulating miR-21 and up-regulating TIMP-3 and RECK. We further confirmed in rats that the microvascular density of precancerous lesions decreased significantly after external use of RUc, which may be related to the inhibition of Ras/Raf/MEK/ERK signaling pathway related proteins. Presumptively, RUc may inhibit the angiogenesis of breast precancerous lesions by inhibiting Ras/Raf/MEK/ERK signaling pathway, thus relieving the inhibition of miR-21 on TIMP-3 and RECK, then down-regulating the secretion of angiogenic factors.

Evaluation of Precancerous Breast Lesion Upgrade Rate

Background: Breast imaging guided core-needle biopsy enable the assessment of suspected precancerous lesions. In some precancerous lesion there is a risk of upgrading to cancer after surgical removal. This study was conducted to determine the upgrading rate of CNB-diagnosed precancerous breast lesions. Methods: A retrospective study was conducted to examine the data of patients who had undergone core needle biopsy from April 2016 to March 2019 at the Radiology Department of the Breast Clinic of Motamed Cancer Institute and whose pathological reports were indicative of a precancerous lesion such as atypical ductal hyperplasia, sclerosing adenosis, flat epithelial atypia or papillary lesion and had undergone surgery for this lesion. The upgrading rate and its related factors such as the size of the lesion, patient’s age, family history of breast cancer and method of core-needle biopsy were analyzed in SPSS software. Results: A total of 241 patients were recruited with a pathological report of pre-cancerous predisposing lesions. The mean age of the patients was 42.14 years and the highest upgrading rates in the analysis were observed for papillary lesion (19.3%) and atypical ductal hyperplasia, (21.4%), while the upgrading rates were (1.2% ) for sclerosing adenosis and (0%) for flat epithelial atypia. Data analysis showed that the lesions’ upgrading rate correlated with the lesion’s size (P=0.005).Conclusion: The findings of this study showed that size of the lesions increase the risk of upgrading to cancer, which is much higher in papillary lesion and atypical ductal hyperplasia compared to sclerosing adenosis and flat epithelial atypia. It seems that surgical excision of the entire lesion in patients with larger mass size may decrease the upgrading rate of cancer. Conducting specific studies on each distinct lesion can help yield more conclusive results.

Retrospective Analysis of COVID-19 Pandemic Impact on Breast Cancer Screening Rates in Northwest Indiana

Background: Few changes to healthcare delivery during the COVID-19 pandemic altered pre-pandemic diagnostic testing as much as those made to cancer screening. Several studies show that screening volumes decreased by as much as 80% across multiple modalities and cancer types in the spring of 2020. These studies examined large hospital systems in the American East and West, but communities with predominantly Black populations like Gary, Indiana, have been absent from this research.
 Methods: Our study captures how the COVID-19 pandemic affected access to diagnostic screening for cancerous and precancerous breast lesions through mammography using patient-level data. “Hospital A” provided data from 17,973 mammography encounters that occurred between March 2019 and June 2021. Screening volumes from the eight-week period from March 23rd and May 17th in 2020, the period elective procedures were suspended, was compared to three other distinct periods: the previous 8-week period, the next 8-week period, and the same 8-week period from 2019.
 Results: From the 17,973 encounters, the average patient age was 61.7 (SD 11.4) years, 61.0% of patients paid with Medicare or Medicaid, and 66.0% of patients identified as Black. Despite performing a weekly average of 190 (12.3) mammograms during the 2019 baseline period and 158 (16.1) mammograms in the eight weeks preceding the COVID-19 pandemic, the weekly average fell to 13 (22.4) mammograms during the study period with zero occurring in a four-week stretch. Fortunately, volume returned sharply to near pre-pandemic levels in the eight weeks following the study period with 139 (18.9) average weekly mammograms.
 Conclusion: Despite a 93% year-over-year decrease in mammography during the height of the pandemic, volume returned in the summer of 2020. Concerning, however, is that average monthly volume (582 (88.5) mammograms) in the first six months of 2021 remains 22.1% lower than 2019 numbers (747 (66.7) mammograms).

Based on BATMAN-TCM to Explore the Molecular Mechanism of Xihuang Pill Regulating Immune Function to Treat Breast Precancerous Lesions.

ObjectiveThe specific mechanism of Xihuang Pill in the treatment of breast precancerous lesions and breast cancer has not yet been elucidated.MethodsIn our study, BATMAN-TCM (a Bioinformatics Analysis Tool for Molecular mechanisms of Traditional Chinese Medicine) was used to forecast the relationship among chemical components, immune targets, and diseases of each herb in Xihuang Pill and constructed a component-target-disease network. Taking breast precancerous lesion model rats as the research object, the molecular mechanism of Xihuang Pill regulating immunity was analyzed.ResultsBATMAN-TCM prediction showed that 309 genes were enriched in the biological process of “immune system response”, which was the target of Xihuang Pill to regulate the immune system. The target of breast cancer disease and the genes related to Xihuang Pill’s immune system response were crossed, and 88 cross genes were obtained. According to the enrichment results of GO/KEGG pathway, T cell activation was found to be the most relevant. We select Th1 cells (IL-2, IFN-γ) and Th2 cells (IL-4, IL-10) among them for animal experiment verification. The results show that Xihuang Pill can upregulate the serum IFN-γ and IL-2 levels, reduce the IL-4 and IL-10 levels, and regulate the balance of Th1/Th2 cells in the peripheral blood of rats with breast precancerous lesions.ConclusionXihuang Pill targets a variety of immune-related molecules related to breast precancerous lesions and is a traditional Chinese medicine formula that effectively regulates immune function.

RhoGAP19D inhibits Cdc42 laterally to control epithelial cell shape and prevent invasion.

Cdc42-GTP is required for apical domain formation in epithelial cells, where it recruits and activates the Par-6-aPKC polarity complex, but how the activity of Cdc42 itself is restricted apically is unclear. We used sequence analysis and 3D structural modeling to determine which Drosophila GTPase-activating proteins (GAPs) are likely to interact with Cdc42 and identified RhoGAP19D as the only high-probability Cdc42GAP required for polarity in the follicular epithelium. RhoGAP19D is recruited by α-catenin to lateral E-cadherin adhesion complexes, resulting in exclusion of active Cdc42 from the lateral domain. rhogap19d mutants therefore lead to lateral Cdc42 activity, which expands the apical domain through increased Par-6/aPKC activity and stimulates lateral contractility through the myosin light chain kinase, Genghis khan (MRCK). This causes buckling of the epithelium and invasion into the adjacent tissue, a phenotype resembling that of precancerous breast lesions. Thus, RhoGAP19D couples lateral cadherin adhesion to the apical localization of active Cdc42, thereby suppressing epithelial invasion.

Clinicopathological Significances of Cancer Stem Cell-Associated HHEX Expression in Breast Cancer.

Aberrant expression of the transcription factor hematopoietic ally expressed homeobox/proline-rich homeodomain (HHEX/PRH) is implicated in numerous cancers. However, the association of HHEX with breast cancer (BC) remains unclear. In this study, HHEX mRNA and protein expression were analyzed using the Oncomine, UALCAN, GEPIA, TCGAportal, and HPA databases. We evaluated the effect of HHEX on clinicopathological parameters using Kaplan–Meier plotter, OncoLnc, TCGAportal, PROGgeneV2, and BC-GenExMiner. Western blotting was performed to compare the level of HHEX in breast samples of Tientsin Albino 2 mice, human breast precancerous lesions, benign breast tumors, and BC. The correlation between HHEX and cancer stem cells was investigated using the GEO (GSE52327 and GSE94865) and GEPIA datasets. Networks between HHEX and survival-related gene marker sets and microRNAs were analyzed using GEPIA, StarBase, and Cytoscape. Results of this study showed that HHEX expression in BC was significantly lower than those in breast precancerous lesions and benign breast tumors at both mRNA and protein levels. BC patients with lower HHEX expression had significantly worse overall survival and disease-free survival. Moreover, HHEX significantly affected the clinicopathology of BC. Specifically, low HHEX expression was correlated with the following groups of patients: age ≤51 years, ER-negative or PR-negative patients, HER-2 positive, triple-negative breast cancer, and basal-like BC. Immunohistochemical analysis of the breast samples showed significant differences of HHEX staining index (P < 0.001) among the three groups. To further investigate the mechanism, we determined the intersection of differentially expressed genes related to BC stem cells and those genes after HHEX expression was altered. This led to the identification of four potentially regulated genes-CXL12, BLNK, PAG1, and LPXN. Using StarBase and km-plotter, the negative regulation of HHEX expression and survival trends, including miR-130b, miR-30e, and miR-301b were joined into miRNA-HHEX-mRNA potential regulatory network. The abilities of proliferation, migration and invasion increased in MDA-MB-231 and BT-549 breast cancer cell lines after HHEX down expression and decreased after HHEX overexpression compared them in the control cells. In conclusion, these data suggest that HHEX expression is downregulated in BC and HHEX may regulate the development of BC through the stem cell-related genes.

Spatiotemporal strategies to identify aggressive biology in precancerous breast biopsies.

Over 90% of breast cancer is cured; yet there remain highly aggressive breast cancers that develop rapidly and are extremely difficult to treat, much less prevent. Breast cancers that rapidly develop between breast image screening are called “interval cancers.” The efforts of our team focus on identifying multiscale integrated strategies to identify biologically aggressive precancerous breast lesions. Our goal is to identify spatiotemporal changes that occur prior to development of interval breast cancers. To accomplish this requires integration of new technology. Our team has the ability to perform single cell in situ transcriptional profiling, noncontrast biological imaging, mathematical analysis, and nanoscale evaluation of receptor organization and signaling. These technological innovations allow us to start to identify multidimensional spatial and temporal relationships that drive the transition from biologically aggressive precancer to biologically aggressive interval breast cancer.This article is categorized under:Cancer > Computational ModelsCancer > Molecular and Cellular PhysiologyCancer > Genetics/Genomics/Epigenetics

OP0070 THE RISK OF PRECANCEROUS LESIONS OF THE BREAST AND CERVIX UTERI IN PATIENTS WITH AUTOIMMUNE RHEUMATIC DISEASES: A NATIONWIDE POPULATION STUDY IN TAIWAN

Background:Precancerous lesions are pathologically atypical tissues which share part of abnormal features of cancerous tissue under microscopic examination but lack the ability of uninhibited growth and distant metastasis. Some of the measures to screen for precancerous tissues have gained popularity because supporting evidence indicates the beneficial effects on cancer incidence and mortality [1, 2]. However, the roles of these screenings and the risk of precancerous lesions in patients with autoimmune diseases have not been clarified. We aim to exam the risk of precancerous lesions among different autoimmune diseases.Objectives:To determine whether the Taiwanese autoimmune rheumatic diseases (ARDs) patients have a higher risk of precancerous lesions of the breast and cervix uteri.Methods:The Taiwan national breast cancer screening program provides biennially mammography for women above 45 years old or with a positive family history of breast cancer above 40 years old. The national cervical cancer screening program provides Pap smear test once every three years for women age above 30 years old. Using the National Health Insurance (NHI) database, we identified a cohort of 6 different groups of ARDs patients in Taiwan between 2004 and 2014. We linked the data from the national screening program of breast and cervical cancer and the NHI database to estimate the standardized incidence ratios (SIRs) of precancerous lesions (atypical lobular and ductal hyperplasia of the breast, carcinoma in situ of the breast, cervical intraepithelial neoplasia 1 to 3 of cervix uteri and carcinoma in situ of cervix uteri) in patients with ARDs compared with the general population.Results:From 2004-2014, we identified 64,904 patients with autoimmune diseases. Table 1 shows the number of patients receiving the screening programs. The standardized incidence ratio (SIR) of precancerous lesion of the breast was elevated in patients with rheumatoid arthritis (SIR, 2.21; 95% CI, 1.21-3.46) and Sjögren syndrome (SIR, 5.77; 95% CI, 2.63-9.85). The incidence of precancerous lesion of cervix uteri was elevated in patients with surveyed ARDs compared with the normal population, particularly for patients with systemic lupus erythematosus (SIR 28.94; 95% CI, 24.52-33.70) and inflammatory bowel disease (SIR, 27.50; 95% CI, 7.40-56.32) (Table 2).Table 1.Breast screen and Pap smear test in patients with autoimmune rheumatic diseasesRheumatoid arthritis (n=28289)Systemic lupus erythematosus (n=11609)Sjögren syndrome (n=17647)Systemic sclerosis (n=1489)Vasculitis(n=3050)Inflammatory bowel disease (n=2820)Female patients21199980815785104312251034Breast screening (n, %)6296 (29.70%)1382 (14.09%)4737 (30.01%)276 (26.46%)67 (5.47%)215 (20.79%)Pap smear (n, %)12827 (60.51%)6495 (66.22%)9961 (63.10%)670 (64.24%)1114 (90.94%)665 (64.31%)Table 2.Standardized incidence ratio (SIR) of precancerous lesion of the breast and cervix uteri in patients with autoimmune rheumatic diseasesPrecancerous lesion of BreastPrecancerous lesion of CervixSIR (95% CI)SIR (95% CI)Rheumatoid arthritis2.21 (1.21-3.46)5.32 (4.25-6.50)Systemic lupus erythematosus1.34 (0.27-2.93)28.94 (24.52-33.70)Sjögren syndrome5.77 (2.63-9.85)8.32(5.72-11.34)Systemic sclerosis6.45 (0.72-15.54)7.93 (2.90-14.80)Vasculitis0.007.68 (1.54-16.83)Inflammatory bowel diseases0.0027.50 (7.40-56.32)Conclusion:Precancerous lesions in the breast and cervix uteri were higher in female patients with ARDs and they should receive stringent screening program.

Effect of Xihuang Pill on microcirculation in DMBA combined estrogen and progesterone induced breast precancerous lesions rats

Objective: To observe the effect of Xihuang Pill on microcirculation in 7,12-dimethylbenzoanthracene (DMBA) combined estrogen and progesterone induced breast precancerous lesions rats. Method: DMBA combined estrogen and progesterone were used to establish the model of breast precancerous lesions for 10 weeks in SD rats, then the low, medium and high dose Xihuang Pill (0.27, 0.55, 1.37g·kg−1) was given intragastric administration, and tamoxifen (4 mg·kg−1) was given intragastric administration as a positive control after the breast precancerous lesions models established successfully. The breast microcirculation was measured by laser Doppler flowmetry (LDF) in rats after 4 weeks of Xihuang Pill and tamoxifen intragastric administration. Result: Compared with the normal control group, the microcirculation perfusion of breast in the disease model group decreased significantly (P < 0.05). Compared with the disease model group, the breast microcirculation perfusion in each dose group of Xihuang Pill increased significantly (P < 0.05). Conclusion: The mechanism of Xihuang Pill in the treatment of breast precancerous lesions may be related to the improvement of breast microcirculation.

Acetyl-11-keto-β-boswellic Acid Inhibits Precancerous Breast Lesion MCF-10AT Cells via Regulation of LINC00707/miR-206 that Reduces Estrogen Receptor-α.

PurposeAcetyl-11-keto-β-boswellic acid (AKBA) has therapeutic effects on a range of diseases, including tumours. lncRNAs, as competing endogenous RNAs (ceRNAs), can interact with miRNAs to regulate the expression of target genes, which can affect the development of tumors. Here, we examined the effects of AKBA on breast precancerous lesions MCF-10AT cells.MethodsThe expression profiles of breast cancer (BC) tissue were collated from The Cancer Genome Atlas (TCGA), and the lncRNA-miRNA-mRNA ceRNA network was constructed. AKBA targets were predicted by network pharmacology. The expression of long intergenic nonprotein-coding RNA 707 (LINC00707), miR-206 and ER-α was determined by qRT-PCR. Cell viability, apoptosis and cycle were assessed by CCK-8 and flow cytometry. Protein levels were measured by Western blotting.ResultsA total of 3205 differentially expressed mRNAs, 104 miRNAs, and 605 lncRNAs were identified. The ceRNA network consisting of 9 lncRNAs, 15 miRNAs and 82 mRNAs was constructed. We found that LINC00707 was up-regulated and miR-206 was down-regulated in MCF-10AT cells. Transfected si-LINC00707 could inhibit cell proliferation, induce cell apoptosis and cycle arrest of MCF-10AT cells. In addition, network pharmacology predicted that AKBA may regulate the ESR1 in the treatment of BC. Our research demonstrated that AKBA could induce cell apoptosis and G1-phase arrest and inhibit ER-α expression via LINC00707/miR-206 in MCF-10AT cells.ConclusionAKBA inhibited MCF-10AT cells via regulation of LINC00707/miR-206 that reduces ER-α.

Xiaotan Jieyu Prescription Alleviates Breast Precancerous Lesions through PI3K/Akt Signaling Pathway.

Methods The successfully established breast precancerous lesion rat model and normal healthy rats were randomly assigned into the blank (BLA), model (MOD), XTJY-low (LD), XTJY-medium (MD), XTJY-high (HD), and tamoxifen (TAM) groups. Different concentrations of XTJY and saline were supplied by intragastric administration for 4 consecutive weeks to assess the protective effect of XTJY on the progress of the breast precancerous lesion in rats involving the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Results In this study, it determined that 10 mg/each rat DMBA-combined estrogen and progesterone induction for 10 weeks was the optimal condition for the establishment of the breast precancerous lesion rat model. In vivo administration of XTJY or TAM was found to inhibit the development of the breast precancerous lesion, and the occurrence rate of breast invasive carcinomas was decreased by about 50%. Furthermore, XTJY or TAM markedly reduced protein expressions of PI3K and p-Akt and increased protein expressions of PTEN. Conclusion These data indicated that XTJY can significantly alleviate the development of breast precancerous lesions by inhibiting the activation of the PI3K/Akt signaling pathway. XTJY may be a promising drug for the treatment of precancerous lesions in breast cancer.