Stages Of Cancer Development Research Articles

Milk fermented by Lactobacillus casei CRL431 modifies cytokine profiles associated to different stages of breast cancer development in mice.

Breast cancer is one of the leading causes of death worldwide. It is recognised that immune system influences its promotion, progression, and metastasis, as well as their responsiveness to therapies. Previously, it was reported that milk fermented by Lactobacillus casei CRL431 decreased tumour growth and metastasis in a mouse breast cancer model, through the modulation of the host immune response. The aim of the present work was to analyse the systemic immune response induced by the administration of probiotic fermented milk (PFM) at different stages of cancer development, evaluating cytokines produced by splenocytes stimulated in vitro with 4T1 tumour cells, or its conditioned medium (CM). Groups of healthy mice and mice bearing 4T1 tumour or suffering metastasis after tumour surgery were studied. Results showed that at the early stages, PFM maintained pro-inflammatory response associated to the delay or the inhibition of tumour growth. PFM administration to mice bearing tumour maintained an important inflammatory response; however, in contrast to the milk group, this response was regulated to avoid exacerbation of inflammation. In the metastasis model, the benefits of PFM were associated to avoid the immunosuppression associated to high interleukin-10 levels. In conclusion, as cancer cells induce modifications of the immune response to favour their own growth at each stage of cancer development, PFM administration stimulated different profile of cytokines to respond to these modifications and fight against cancer cells.

Characterization of mutational processes in ER+ metastatic breast cancer.

1019 Background: Diverse mutational processes are active at different stages of cancer development and cause the mutational burden in cancer cells. These processes leave distinctive signatures, characterized by varying frequencies of nucleotide substitutions and their flanking base-pairs. Mutational signatures found in early stage breast cancer have been described, but less is known about the mutational processes in metastatic breast cancer (MBC). Methods: We performed whole exome sequencing (WES) on 209 metastatic tumor biopsies from patients with ER+ MBC. In a subset of patients, we obtained and performed WES on the matched primary biopsy (n = 62). Decomposition of mutational signatures was done by determining the linear combination of 30 previously reported mutational signatures (Alexandrov et al., 2013) that most accurately reconstructs the mutational profile of each tumor sample. For comparison, signature decomposition was also performed on 695 treatment-naïve primary ER+ breast cancers form The Cancer Genome Atlas (TCGA). Results: Cohort-level comparison of signature activity between our cohort of MBC biopsies versus the primary ER+ breast cancers from TCGA demonstrated enrichment of Signature 13 in MBC samples (q = 0.002), attributed to activity of the APOBEC family of cytidine deaminases and implicated in resistance to endocrine therapies. Activity of Signature 22, associated to activity of the nucleotide-excision repair mechanism, was depleted in MBC tumors relative to TCGA ER+ breast tumors (q = 0.02). Decomposition of mutational signatures at the clone level in the subset of patients with both metastatic and matched primary samples allowed us to infer signatures acquired in the metastatic setting. Among mutations in acquired clones, we found enrichment of APOBEC signatures (Sig. 2, q = 0.018; Sig. 13, q = 0.003). Conversely, activity of Signature 1, attributed to the normal aging process, was enriched in mutations shared between primary and MBC samples (q = 0.004). This suggests that mutations developed early in tumor evolution may be driven primarily by natural processes, while later mutations may reflect selective pressures imposed by therapies and cellular defects acquired during disease progression. Conclusions: The profile of somatic mutations in MBC differs from early stage breast cancer. APOBEC-related mutations arising late during tumor evolution are one possible mechanism for this difference. Further studying the associations between clinical features and therapies to mutational processes could inform design of clinical trials and management of MBC.

Zinc finger proteins and regulation of the hallmarks of cancer.

Zinc finger proteins (ZFPs) form one of the largest families of transcription factors in human genetics, via their conserved zinc finger motifs. ZFPs function in many biological processes including development, differentiation, metabolism and apoptosis. In addition, recent studies have demonstrated that ZFPs are closely associated with different stages of cancer development. One of the hallmarks of cancer is altered signal transduction cascades and an understanding of the changes in these pathways is essential for targeted cancer therapy. In this review, we discuss examples of ZFPs involved in development and progression of several types of cancer, which can provide new insights into cancer treatment.

Primary tumor-induced immunity eradicates disseminated tumor cells in syngeneic mouse model

Although clinically apparent metastasis is associated with late stages of cancer development, micro-metastatic dissemination may be an early event. However, the fate of these early disseminated tumor cells (DTC) remains elusive. We show that despite their capacity to disseminate into secondary organs, 4T1 tumor models develop overt metastasis while EMT6-tumor bearing mice clear DTCs shed from primary tumors as well as those introduced by intravenous (IV) injection. Following the surgical resection of primary EMT6 tumors, mice do not develop detectable metastasis and reject IV-injected tumor cells. In contrast, these cells readily grow and metastasize in immuno-deficient athymic or Rag2−/− mice, an effect mimicked by CD8+ T-cell depletion in immunocompetent mice. Furthermore, recombinant G-CSF or adoptive transfer of granulocytic-MDSCs isolated from 4T1 tumor-bearing mice, induce metastasis by suppressing CD8+ T-cells in EMT6-primed mice. Our studies support the concept of immune surveillance providing molecular insights into the immune mechanisms during tumor progression.

Molecular Targets, Anti-cancer Properties and Potency of Synthetic Indole-3-carbinol Derivatives.

The indole-3-carbinol (I3C) displays anti-cancer/proliferative activities against human cancer cells. Cellular proliferation is an event associated with the progress and its continuation. This manifest is described by variation in expression and/or functions of genes that are related with cell cycle relevant proteins. The constitutive activation of several signal transduction pathways stimulates cells proliferation as well. The immediate stages in cancer development are accompanied by a fibrogenic response and the progression of the hypoxic environment is in favor of survival and proliferatory functions of cancer stem cells. A main part for prevention of in cancer cells death may manifest through altering cell metabolism. Cellular proliferation and metastasis are reported to be supported with increased generation of responsible hormones (in hormone dependent malignancies), and further promotion the angiogenesis, with epithelial to mesenchymal transition. This may be facilitated by progression of autophagy phenomenon, as well as via taking cues from neighboring stromal cells. Several signaling pathways in association with various factors specific for cellular viability, including hypoxia inducible factor 1, NF-κB, insulin-like growth factor 1 (IGF-1) receptor, Human foreskin fibroblasts (HFF-1), phosphoinositide 3 kinase/Akt, Wnt, cell cycle related protein, with androgen and estrogen receptor signaling are reported to be inhibited by I3C. These evidences, in association with bioinformatics data represent very important information for describing signaling pathways in parallel with molecular targets that may serve as markers for early diagnosis and/or critical targets for designing and development of novel therapeutic regimes alone or combined with drugs, to prevent tumor formation and further progression. In particular, I3C and DIM have been extensively investigated for their importance against numbers human cancers both in vitro and in vivo. We aimed the present manuscript, current study, to review anticancer properties and the miscellaneous mechanisms underlying the antitumorigenicity in an in-depth study for broadening the I3C treating marvel.

Differential expression of S1P receptor subtypes in human bladder transitional cell carcinoma.

Sphingosine 1 phosphate (S1P), S1P receptors (S1PRs) and their signaling pathways play an important role in the fate of cancer cells. The expression pattern of S1PR subtypes (S1PR1-S1PR5) may alter in cancer development stages, depending on the origin and the pathologic features of tumors. The present study aimed to examine the relationship between plasma S1P levels and the expression of S1PR subtypes in bladder tumors. These changes were evaluated in terms of the pathologic grades and stages of human bladder cancer samples. For this, tumor biopsies from 41 new bladder cancer patients as well as 26 normal-looking bladder tissues were collected and processed for immunohistochemistry (IHC) and quantitative real-time RT-PCR of S1PR subtypes. Plasma S1P level was measured using liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that tissue S1PR1, S1PR2 and S1PR3 are over-expressed in all tumors regardless of their pathological grade (~ 3, ~ 6 and ~ 104 folds, respectively). These results were corroborated by IHC data showing accumulation of S1PR subtypes 1 and 2 in the tissues. Plasma S1P in the plasma samples from patients was in the range of control samples (Controls; 256 ± 47; patients, 270 ± 41). Overexpression of S1PR1, S1PR2 and S1PR3 in bladder tumor biopsies which were corroborated with the pathological grades and stages may suggest that S1PR profile in tumor biopsies is a promising marker in the diagnosis of bladder carcinoma.

Assessment of apelin, apelin receptor, resistin, and adiponectin levels in the primary tumor and serum of patients with esophageal squamous cell carcinoma

Disturbances in adipokine secretion are associated with the risk of cancer growth and progression. The aim of the study was to evaluate the mRNA expression and protein levels of apelin, the apelin receptor, resistin, and adiponectin in the tumor tissues of surgically treated esophageal squamous cell carcinoma (ESCC) patients. Concentrations of serum adipokines were assessed in relation to ESCC progression. The study group consisted of 53 patients with ESCC and 27 controls. In the ESCC group, 27 patients were surgically treated and 26 were treated with palliative procedures. RT-PCR and ELISA tests were used to measure the mRNA expression and protein level of adipokines in tissues and their concentration in serum. We found that mRNA expression and protein concentrations of apelin, the apelin receptor and resistin were significantly higher in tumor tissue than in control tissue. The protein concentration of apelin were significantly increased in the tumors of patients with lymph node metastasis (p < 0.005). Circulating levels of apelin, the apelin receptor and resistin were significantly higher in the cancer patients than in controls (p < 0.05 for all). The concentration of serum apelin receptor significantly decreased in patients with stage IV cancer, the presence of lymph node or distant metastasis (p < 0.05). Apelin may participate in lymphangiogenesis and the progression of ESCC. The apelin receptor is intensely produced in the early stage of cancer development and it may take part in the carcinogenic processes of ESCC.

Schwann cells shape the neuro-immune environs and control cancer progression.

At present, significant experimental and clinical data confirm the active involvement of the peripheral nervous system (PNS) in different phases of cancer development and progression. Most of the research effort focuses on the impact of distinct neuronal types, e.g., adrenergic, cholinergic, dopaminergic, etc. in carcinogenesis, generally ignoring neuroglia. The very fact that these cells far outnumber the other cellular types may also play an important role worthy of study in this context. The most prevalent neuroglia within the PNS consists of Schwann cells (SCs). These cells play a substantial role in maintaining homeostasis within the nervous system. They possess distinct immunomodulatory, inflammatory and regenerative capacities-also, one should consider their broad distribution throughout the body; this makes them a perfect target for malignant cells during the initial stages of cancer development and the very formation of the tumor microenvironment itself. We show that SCs in the tumor milieu attract different subsets of immune regulators and augment their ability to suppress effector T cells. SCs may also up-regulate invasiveness of tumor cells and support metastatic disease. We outline the interactive potential of SCs juxtaposed with cancerous cells, referring to data from various external sources alongside data of our own.

The Anticancer Activity of Caffeine - A Review

The cancer burden statistics have been on the rise between the years 2008 and 2018. There has been an increase in the incidence and mortalities of cancers within this period. These statistics justify the sustained increase in the study and exploration of more agents with significant anticancer activity. Compounds of natural origin, such as caffeine, a widely known member of the xanthine family of purines fall under this category. It is a popular component of beverages and medications used in contemporary times. This review aims to elucidate on the anticancer activities attributed to caffeine. Caffeine consumption has been shown to have anticancer benefits from epidemiological evidences. It prevents the initiation of carcinogenesis and has antitumor activity. Caffeine also has significant anticancer activity against animal and cultured cell line models of cancer. The cytotoxic effects of some anticancer drugs have also been improved by combination with caffeine. Furthermore, caffeine and related xanthine derivatives have also been applied in experimental chemotherapy. Some molecular pathways have been implicated in these activities related to apoptosis and DNA damage repair pathways. These studies outline the beneficial anticancer effects of caffeine against the different stages of cancer development.

Quantification of CYFRA21-1 antigen in non-small cell lung cancer by Phage Display Real-time Immuno-PCR Method

Lung cancer is one of the most severe and frequent types of cancer in men, from 50 to 70 years of age. There are two main types: small cell lung cancer and non-small cell lung cancer. Non-small cell lung cancer (NSCLC) accounts for about 80%. CYFRA21-1 antigen is associated explicitly with NSCLC according to recent studies on lung cancer and the mechanism of lung cancer generation. In the serum of healthy people, CYFRA21-1 antigen content makes up ≤ 3.3 ng/mL. However, for those who appear NSCLC, this content increases very quickly. The concentration of CYFRA21-1 antigen in serum is directly proportional to the stage of cancer development. The higher the concentration, the shorter the lifetime of the patient. Therefore, it is possible to study the increase in serum CYFRA21-1 levels as a sign of early identification of NSCLC. The Phage Display Real-time Immuno-PCR method (PDRTI-PCR) was used in this study to quantify CYFRA21-1 antigen in NSCLC patients. PDRTI-PCR method has a combination of specificity of ELISA with sensitivity of Real-time PCR technique and phage display technique. Quantification of CYFRA21-1 antigen by PDRTI-PCR method provides reliable sensitivity and accuracy, which is the basis for creating an NSCLC early diagnosis kit.

Mode of action of tocotrienol as anticancer

Tocotrienols are fat soluble substances members of the vitamin E family with the main properties of antioxidant. They are composed of the chiral center of chromanol ring with polypreniyl side chains. Research suggests that tocotrienols have a number of health benefit, and one of them as an anticancer agent. As an anticancer, tocotrienols could perform in different processes of the multi stages of cancer development and interact with other anticancer medicines and other bioactive substances, suchs geneistein, lovastin, hydroxychavicol, 6- gingerol and sesamin. The anticancer activities occur through their roles as antioxidant, coenzyme, gene expression regulator, and preventing cholesterol synthesis by inhibiting the expression of HMGCR enzyme after transcription, through this method, tocotrienols could control the cholesterol level of cancer cells and prevent the growth of the cancer. Tocotrienols target several signalling pathways at cellular and molecular levels.

Automated Tumor Segmentation Based on Hidden Markov Classifier using Singular Value Decomposition Feature Extraction in Brain MR images

ntroduction: Diagnosing brain tumor is not always easy for doctors, and existence of an assistant that facilitates the interpretation process is an asset in the clinic. Computer vision techniques are devised to aid the clinic in detecting tumors based on a database of tumor contained images. These precise techniques open up the way for recognizing a tumor even in the early stages of cancer development depicted as very low contrast object in an image. To this end, at first a set of similarity measures are calculated for each pixel in the image database. Then, this dataset is fed into a classifier that defines the mathematical rules necessary for making decision about a new image. After defining the rules, a model is formed which is ready to make decisions for new images outside the database. This decision is accompanied with an accuracy which is calculated in the end as the classifier performance measures. Materials and Methods: In this study, Singular Value Decomposition – SVD – method is used as a tool to extract similarity measures for each malignant image in the database. These measures form a matrix with which the classifier is trained. The classifier in this study, is a model based on Hidden Markov Random Field – HMRF – idea, that utilizes Bayes’ rule and maximum a posteriori criterion to obtain labels for each pixel and making decisions about he new images respectively. After sorting the new image as either malignant or not, the malignant image goes through a wavelet process for tumor segmentation. In this section, the image is transformed into a multilevel wavelet structure. Image segmentation is done using direct and inverse wavelet transform. Results: The classification performance is done quantitatively and qualitatively by calculating Volume Overlap Ratio (VOR), Recognition Rate (RR), True Negative Rate (TNR), True Positive Rate (TPR), Accuracy (ACC), Sensitivity and Specificity parameters, and 5 output images respectively. Also, a qualitative comparison is made between MRF, HMRF and morphological image segmentation methods. Conclusion: The application of HMRF-Wavelet pattern recognition has been investigated in this work. VOR, RR, TNR, TPR, ACC, Sensitivity and Specificity are calculated, and most values have been reported as over 95% for five test images. Despite the complexity of the HMRF statistical modeling, acceptable performance measure values indicate the sufficiency of this algorithm.

A cancer associated somatic mutation in LC3B attenuates its binding to E1-like ATG7 protein and subsequent lipidation

ABSTRACTMacroautophagy/autophagy is a conserved catabolic process that maintains cellular homeostasis under basal growth and stress conditions. In cancer, autophagy can either prevent or promote tumor growth, at early or advanced stages, respectively. We screened public databases to identify autophagy-related somatic mutations in cancer, using a computational approach to identify cancer mutational target sites, employing exact statistics. The top significant hit was a missense mutation (Y113C) in the MAP1LC3B/LC3B (microtubule associated protein 1 light chain 3 beta) protein, which occurred at a significant frequency in cancer, and was detected in early stages in primary tumors of patients with known tumor lineage. The mutation reduced the formation of GFP-LC3B puncta and attenuated LC3B lipidation during Torin1-induced autophagy. Its effect on the direct physical interaction of LC3B with each of the 4 proteins that control its maturation or lipidation was tested by applying a protein-fragment complementation assay and co-immunoprecipitation experiments. Interactions with ATG4A and ATG4B proteases were reduced, yet without perturbing the cleavage of mutant LC3B. Most importantly, the mutation significantly reduced the interaction with the E1-like enzyme ATG7, but not the direct interaction with the E2-like enzyme ATG3, suggesting a selective perturbation in the binding of LC3B to some of its partner proteins. Structure analysis and molecular dynamics simulations of LC3B protein and its mutant suggest that the mutation changes the conformation of a loop that has several contact sites with ATG4B and the ATG7 homodimer. We suggest that this loss-of-function mutation, which attenuates autophagy, may promote early stages of cancer development.

Transforming Growth Factor-Beta and Urokinase Type Plasminogen Interplay in Cancer.

Transforming growth factor-beta (TGF-β) is well recognized as playing a double role in tumor progression. Its antitumor role takes place in the early stages of cancer development, when TGF-β acts as a repressor of epithelial tumor growth. In advanced stages of cancer development, TGF-β has a tumor stimulating role, acting concomitantly with the increase of cancer cell migration and metastasis. One of the critical features of cancer cells is their ability to migrate and invade the surrounding tissues leading to metastases in different organs. Cancer cells that leave the tumor to infiltrate neighboring tissues and ultimately overtake a distant organ, need a complex and fine-regulated mechanism to move through the barrier imposed by the extracellular matrix (ECM). Therefore, cancer cells express a set of proteinases which are involved in the degradation and turnover of ECM. In particular, the urokinase type plasminogen activator (uPA) and the uPA cell surface receptor play key cellular roles in the enhancement of cell malignance during tumor progression. In normal cells uPA system is finely regulated, while in tumor cells its expression and activity are dysregulated in a way to enhance cells' invasion capacity during tumor progression. TGF-β strongly regulates uPA in cancer from transcriptional expression to enzyme activity. In turn, uPA participates in the activation of secreted latent TGF-β, thus producing a malicious loop which contributes to tumor progression and metastasis. In this review we will analyze the main molecular mechanisms implicated in uPA regulation by TGF-β. Moreover, the specific roles and interaction between TGF-β and uPA system in cancer cells and their impact on tumorigenesis will be portrayed.

Emerging microRNAs in cancer diagnosis, progression, and immune surveillance

MicroRNAs (miRNAs) are small noncoding RNAs that function in post-transcriptional regulation of gene expression. Dysregulation of miRNAs has been reported in different stages of cancer development and progression. This dysregulation results in different miRNA profiles between cancer and normal tissues. Many studies have shown a significant correlation between miRNA profile and cancer diagnosis and prognosis. Additionally, since a single miRNA regulates multiple mRNA targets, miRNAs dysregulation can affect several pathways involved in cancer development. Finally, due to their regulatory role in immune cell development, many recent studies have reported that certain miRNAs play key roles in cancer immunology. In this brief review, we discuss the role of miR-21 and miR-375 in the RAS pathway as well as their role in cancer diagnosis and progression, along with the role of other select miRNAs in cancer immune surveillance.

Downregulation of tumor-suppressor gene LHX6 in cancer: a systematic review.

LIM Homeobox 6 (LHX6) encodes a LIM homeodomain transcription factor, contributes to tissue development and morphogenesis, and is mostly expressed in medial ganglionic eminence and odontogenic mesenchyme. However, it has been reported to play a role in cancer progression. This narrative review summarizes literatures that emphasize the molecular regulation of LHX6 in tumorigenesis. In our systematic review, the PubMed database was used for the literature search using the combination of words that included "LHX6" and "cancer". Relevant studies, including in vitro, in vivo experiments, and clinical studies, were analyzed in this review. We found evidences that LHX6 might be important in the inhibition of tumor cell proliferation, growth, invasion, and metastasis through the suppression of Wnt/β-catenin signaling pathway. Moreover, LHX6 is observed to be downregulated in certain types of cancer due to hypermethylation, thus hindering its tumor suppressing ability. In addition, hypermethylation can also be used to determine the stage of cancer development. The downregulation of LHX6 expression might be responsible in promoting cancer progression. Future studies are necessary to investigate the potential of LHX6 as a novel cancer biomarker as well as its therapeutic implications towards certain types of cancer.

Forward and reverse mutations in stages of cancer development

BackgroundMassive occurrences of interstitial loss of heterozygosity (LOH) likely resulting from gene conversions were found by us in different cancers as a type of single-nucleotide variations (SNVs), comparable in abundance to the commonly investigated gain of heterozygosity (GOH) type of SNVs, raising the question of the relationships between these two opposing types of cancer mutations.MethodsIn the present study, SNVs in 12 tetra sample and 17 trio sample sets from four cancer types along with copy number variations (CNVs) were analyzed by AluScan sequencing, comparing tumor with white blood cells as well as tissues vicinal to the tumor. Four published “nontumor”-tumor metastasis trios and 246 pan-cancer pairs analyzed by whole-genome sequencing (WGS) and 67 trios by whole-exome sequencing (WES) were also examined.ResultsWidespread GOHs enriched with CG-to-TG changes and associated with nearby CNVs and LOHs enriched with TG-to-CG changes were observed. Occurrences of GOH were 1.9-fold higher than LOH in “nontumor” tissues more than 2 cm away from the tumors, and a majority of these GOHs and LOHs were reversed in “paratumor” tissues within 2 cm of the tumors, forming forward-reverse mutation cycles where the revertant LOHs displayed strong lineage effects that pointed to a sequential instead of parallel development from “nontumor” to “paratumor” and onto tumor cells, which was also supported by the relative frequencies of 26 distinct classes of CNVs between these three types of cell populations.ConclusionsThese findings suggest that developing cancer cells undergo sequential changes that enable the “nontumor” cells to acquire a wide range of forward mutations including ones that are essential for oncogenicity, followed by revertant mutations in the “paratumor” cells to avoid growth retardation by excessive mutation load. Such utilization of forward-reverse mutation cycles as an adaptive mechanism was also observed in cultured HeLa cells upon successive replatings. An understanding of forward-reverse mutation cycles in cancer development could provide a genomic basis for improved early diagnosis, staging, and treatment of cancers.

Novel frontiers in detecting cancer metastasis.

Cancer microenvironment is the critical battle ground between the cancer cells and host response. Thus, more emphasis is directed to study the relationship between cancer cells and the stromal cells. Multiplex microscopy is an emerging technique in which multiple cell populations within the cancer microenvironment may be stained so that spatial relationship between cancer cells and, in particular, the immune cells may be studied during different stages of cancer development. Recent discovery of mutational burden and neoantigens in cancer has opened new landscapes in the interaction of host immune cells and cancer neoantigens. The emerging role of miRNAs may become an added dimension to study cancer beyond traditional pathway of DNA directed RNA being associated with the malignant behavior of cancer. Circulating tumor cells, cancer markers and ctDNA can be used as markers for circulating cancer cells in the blood. Further studies are needed to validate if liquid biopsy of cancer may become a routine clinical tool to screen cancer or follow patients for recurrence or responses to treatment.

Bioenergetics of life, disease and death phenomena

In this article, some new aspects of unified cell bioenergetics are presented. From the perspective of unified cell bioenergetics certain subsequent stages of cancer development, from initiation stage, through transformation to metastasis, are analyzed. Here we show that after transformation, cancer cells are permanently exposed to reactive oxygen species, that causes continual random DNA mutations and as a result genome and chromosomal destabilizations. The modern cancer attractor hypothesis has been extended in explaining cancer development. Discussion is conducted in light of current cancerogenesis research, including bioenergetic cancer initiation, the somatic mutation theory and the tissue organization field theory. In the article reasons complicating the discovery of patterns of cancer genome changes and cancer evolution are presented. In addition certain cancer therapeutic aspects are given attention to.

Abstract 5054: Transcriptional changes in breast cancer initiation

Abstract Background: Identifying the earliest stages of breast cancer carcinogenesis, present well before any clinical signs of disease, is the necessary underpinning of an effective breast cancer prevention strategy. We propose to elucidate transcriptomic changes occurring in the breast tissue during cancer initiation. by analyzing biospecimens donated by women before any clinical sign of sporadic breast tumor (here labeled “susceptible”). In the present work, we report on the transcriptome differences in the microdissected breast compartments (epithelium, stroma and fat) of susceptible versus healthy premenopausal women. Methods: The specimens were obtained from the Susan G. Komen Tissue Bank at IU Simon Cancer Center. We compared the transcriptome profiles of breast tissues from 7 susceptible and 17 healthy premenopausal women between the age of 34 and 52 years, who were free of breast pathology at the time of donation. Donors in the two experimental groups were matched according to age, racial background and menstrual phase. Differential expression analysis was performed using EdegR. False discovery rate (FDR) was computed from p-values using the Benjamini-Hochberg procedure. Ingenuity Pathway Analysis was used to identify relevant signaling pathways. Because circulating hormones variations during menstrual cycle affect the breast epithelium gene expression, we also examined transcriptome differences independently from the menstrual phase. Results/Discussion: We found 536 transcripts differentially expressed between the two groups (p&amp;lt;0.05). However, only 412 changed independently from the follicular or luteal status. Among these, 130 transcripts (including 1 linRNA) were downregulated, while 282 transcripts (including 6 lincRNAs and 5 miRNAs) were upregulated in the susceptible versus healthy breasts. Among the upregulated genes, we observed three major affected pathways: 1) lipid metabolism, 2) molecular transport, and 3) energy production. When we set a more stringent cutoff (p&amp;lt;0.05, fold change&amp;gt; 2 and FDR&amp;lt;0.2), only 11 genes were differentially expressed between susceptible and healthy controls; these are involved in cellular metabolism (AKR1C1, AKR1C2, and SDR16C5) and cell adhesion and cytoskeleton organization (CNTNAP2 and XIRP2). The transcription repressor ZFP57 was the only downregulated gene (fold change=-29; p=0.0002; FDR=0.09).The study will be soon corroborated with the transcriptome profiling of the other two breast compartments (stroma and fat). Conclusion: This study shows that earliest alterations in breast cancer initiation affect metabolic pathway as well as transcriptional regulation. Interestingly, cell adhesion signaling may also be dysregulated at this early stage of cancer development. The findings will contribute to our understanding of the mechanisms of cancer initiation, as well as the identification of new therapeutic targets and thus, improvement of preventive interventions. Citation Format: Natascia Marino, Rana German, Mariah L. Johnson, Xi Rao, Xiaoling Xuei, Jun Wan, Anna Maria V. Storniolo. Transcriptional changes in breast cancer initiation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5054.