Myoepithelial Cell Differentiation Markers in Ductal Carcinoma in Situ Progression

Abstract

We describe a preclinical model that investigates progression of early-stage ductal carcinoma in situ (DCIS) and report that compromised myoepithelial cell differentiation occurs before transition to invasive disease. Human breast cancer MCF10DCIS.com cells were delivered into the mouse mammary teat by intraductal injection in the absence of surgical manipulations and accompanying wound-healing confounders. DCIS-like lesions developed throughout the mammary ducts with full representation of human DCIS histologic patterns. Tumor cells were incorporated into the normal mammary epithelium, developed ductal intraepithelial neoplasia and DCIS, and progressed to invasive carcinoma, suggesting the model provides a rigorous approach to study early stages of breast cancer progression. Mammary glands were evaluated for myoepithelium integrity with immunohistochemical assays. Progressive loss of the myoepithelial cell differentiation markers p63, calponin, and a-smooth muscle actin was observed in the mouse myoepithelium surrounding DCISinvolved ducts. p63 loss was an early indicator, calponin loss intermediate, and a-smooth muscle actin a later indicator of compromised myoepithelium. Loss of myoepithelial calponin was specifically associated with gain of the basal marker p63 in adjacent tumor cells. In single time point biopsies obtained from 16 women diagnosed with pure DCIS, a similar loss in myoepithelial cell markers was observed. These results suggest that further research is warranted into the role of myoepithelial cell p63 and calponin expression on DCIS progression to invasive disease. Clinical evidence is compelling for histologic progression of breast cancer through atypical hyperplasia, ductal carcinoma in situ (DCIS), invasive ductal carcinoma, and metastatic stages. 1 Such histopathologic progression studies and mutational profiling of epithelial cancers 2,3 suggest that acquisition of invasive potential is a relatively late event. However, genomic data analyses have revealed that most tumor cell gene expression changes occur at the transition from normal to DCIS, with few additional changes in expression occurring at the transition from DCIS to overt invasive disease. 4,5 These observations implicate key roles for nonepithelial cells in progression to invasive disease. 6,7 The lack of relevant model systems has hindered our understanding of the DCIS to invasive transition.The clinical definition of invasive breast cancer is spread of malignant tumor cells from the confines of the mammary duct into the adjacent tissue stroma. In the normal mammary gland, epithelial ductal and alveolar structures are

Reply to the Baader–Meinhof phenomenon in ductal carcinoma in situ of the breast

“…Although we did not specifically draw attention to the changes in the DCIS stroma seen in Figure 1 of our review, we acknowledge the importance of the DCIS microenvironment in determining disease outcome. This has been demonstrated by the work of Van Bockstal et al ., which we cited in our review, and of others investigating the role of myoepithelial cells, stromal proteins and the immune response in DCIS . Indeed, we have published extensively on the role of the tumour microenvironment in DCIS, including angiogenic patterns surrounding DCIS and the significance of the immune infiltrate to prognosis …”

Multiplexed imaging reveals heterogeneity of PI3K/MAPK network signaling in breast lesions of known PIK3CA genotype

“…The role of epithelial-stromal interactions and epithelial-myoepithelial-stromal interactions in cancer progression is increasing recognized, and this interface phosphoprotein signature offers an avenue for further investigation. Analysis of additional lesions and multiplex staining incorporating myoepithelial cell markers (such as p63, calponin, smooth muscle myosin heavy chain) would be a next step to investigate this hypothesis [31, 32]. …”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…Subtending both these layers of cells is a highly specialized layer of extracellular matrix proteins termed the basement membrane (BM). Myoepithelial cells are lost with malignant progression [16][17][18] and are believed to play an important tumor suppressive role in the healthy breast due to their ability to secrete the specialized extracellular matrix proteins of the BM [16,19]. Myoepithelial cells surrounding tumors show a shift in ECM protein secretion, losing expression of tumor-suppressive laminins and increasing expression of collagens [16,20].…”