Abstract
To characterize molecular changes accompanying the stepwise progression to breast cancer and to identify functional target pathways, we performed miRNA and RNA sequencing using MCF10A cell lines based model system that replicates the multi-step progression involving normal, preneoplastic, ductal carcinoma in situ, and invasive carcinoma cells, where the carcinoma most resemble the basal-like subgroup of human breast cancers. These analyses suggest that 70% of miRNA alterations occurred during the initial progression from normal to a preneoplastic stage. Most of these early changes reflected a global upregulation of miRNAs. This was consistent with a global increase in the miRNA-processing enzyme DICER, which was upregulated as a direct result of loss of miRNA let-7b-5p. Several oncogenic and tumor suppressor pathways were also found to change early, prior to histologic stigmata of cancer. Our finding that most genomic changes in the progression to basal-like breast cancer occurred in the earliest stages of histologic progression has implications for breast cancer prevention and selection of appropriate control tissues in molecular studies. Furthermore, in support of a functional significance of let-7b-5p loss, we found its low levels to predict poor disease-free survival and overall survival in breast cancer patients.
Highlights
According to a well-established model of cancer development, sporadic breast cancer develops through progressive accrual of driver molecular aberrations in the normal breast tissue [1]
We were interested in identifying miRNAs that followed one of eight expression patterns: early and continuous increase across the spectrum (G1), early and continuous decrease across the spectrum (G8), early increase followed by a plateau (G2), early decrease followed by a plateau (G7), delayed
We removed 1533 miRNAs that were expressed at the same levels across all of the samples, as these were deemed uninformative for the primary objective of examining the molecular alterations that underlie histologic progression
Summary
According to a well-established model of cancer development, sporadic breast cancer develops through progressive accrual of driver molecular aberrations in the normal breast tissue [1]. On the basis of this model, one would envision early, high-risk lesions to possess a limited amount of molecular alterations, with lesions further down the histologic spectrum (such as ductal carcinoma in situ [DCIS]) showing disproportionally higher rates of mutational change In contrast to this prevailing notion, several recent studies have found a plethora of molecular changes, such as loss of heterozygosity, miRNA, and gene aberrations in normal tissues immediately adjacent to areas of breast carcinoma [2,3,4,5]. To evaluate these two competing models of the molecular evolution across the preneoplastic state, we seek to comprehensively characterize the genomic changes within a model system that has been shown to closely resemble the development of basal-like human breast cancers [6,7,8,9], an aggressive breast cancer subtype. Our objectives are to understand the breadth and timing of molecular alterations and their relationship to well-accepted stages of histologic progression and to identify the functional networks that may suggest opportunities for targeted prevention
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