Abstract
The mechanisms that drive ductal carcinoma in situ (DCIS) progression to invasive cancer are not clear. Studying DCIS progression in humans is challenging and not ethical, thus necessitating the characterization of an animal model that faithfully resembles human disease. We have characterized a canine model of spontaneous mammary DCIS and invasive cancer that shares histologic, molecular, and diagnostic imaging characteristics with DCIS and invasive cancer in women. The purpose of the study was to identify markers and altered signaling pathways that lead to invasive cancer and shed light on early molecular events in breast cancer progression and development. Transcriptomic studies along the continuum of cancer progression in the mammary gland from healthy, through atypical ductal hyperplasia (ADH), DCIS, and invasive carcinoma were performed using the canine model. Gene expression profiles of preinvasive DCIS lesions closely resemble those of invasive carcinoma. However, certain genes, such as SFRP2, FZD2, STK31, and LALBA, were over-expressed in DCIS compared to invasive cancer. The over-representation of myoepithelial markers, epithelial-mesenchymal transition (EMT), canonical Wnt signaling components, and other pathways induced by Wnt family members distinguishes DCIS from invasive. The information gained may help in stratifying DCIS as well as identify actionable targets for primary and tertiary prevention or targeted therapy.
Highlights
There is evidence that all breast cancer subtypes evolve from a non-invasive ductal carcinoma in situ (DCIS) precursor stage [1]
The molecular changes associated with normal, atypical ductal hyperplasia (ADH), and DCIS progressing to invasive cancer were investigated in the same mammary gland in the same dog, using next-generation sequencing
2020, 12, 418 of ADH and DCIS to invasive mammary cancer as compared to normal, 3 of 18 we evaluated the differential gene expression results derived from the union of DESeq2 [19] and EdgeR
Summary
There is evidence that all breast cancer subtypes evolve from a non-invasive ductal carcinoma in situ (DCIS) precursor stage [1]. Seldom encountered before mammographic screening became routine, DCIS accounts for about 20% of breast cancer diagnoses [2]. The current standard of care for all DCIS patients is surgery, radiation, or hormonal therapy. This management approach has good disease-free outcomes, but entails over-treatment in most cases, subjecting women to unnecessary medical and psychological side effects [3,4]. There is an urgent need to understand the natural history of DCIS and to develop methodologies to distinguish non-progressive versus progressive cases
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