Abstract 5054: Transcriptional changes in breast cancer initiation

Abstract

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<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<0.05, fold change> 2 and FDR<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.