Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage

Simple Summary Breast cancer-ductal carcinoma of the breast and invasive ductal carcinoma (IDC)-arises within the confines of the mammary ductal epithelium. Progression to IDC can occur through a pre-invasive, ductal carcinoma in situ stage (DCIS), or in the absence of DCIS. The immune system has recently been identified as a factor in disease progression, highlighting the need for immune-competent mouse models of pre-invasive disease. To model early-stage disease, we tested six distinct murine mammary tumor cell lines injected directly into the mammary ducts of immune-competent mice. We find that all six mouse cell lines bypassed a stable DCIS stage, rapidly progressing to IDC. Similarly, in immune-compromised mice, we observed IDC in the absence of DCIS, suggesting an intact immune system may not play a primary role in early disease progression in these mouse models. These models may be useful for the study of IDC that occur in the absence of DCIS, and in the development of immune therapies. In breast cancer, progression to invasive ductal carcinoma (IDC) involves interactions between immune, myoepithelial, and tumor cells. Development of IDC can proceed through ductal carcinoma in situ (DCIS), a non-obligate, non-invasive stage, or IDC can develop without evidence of DCIS and these cases associate with poorer prognosis. Tractable, immune-competent mouse models are needed to help delineate distinct mechanisms of local tumor cell invasion and prognostic implications. To address these gaps, we delivered murine mammary carcinoma cell lines directly into the main mammary lactiferous duct of immune-competent mice. Using two strains of immune-competent mice (BALB/c, C57BL/6), one immune-compromised (severe combined immunodeficiency; SCID) C57BL/6 strain, and six different murine mammary cancer cell lines (D2.OR, D2A1, 4T1, EMT6, EO771, Py230), we found early loss of ductal myoepithelial cell differentiation markers p63, alpha-smooth muscle actin, and calponin, and rapid formation of IDC in the absence of DCIS. Rapid IDC formation also occurred in the absence of adaptive immunity. Combined, these studies demonstrate that loss of myoepithelial barrier function does not require an intact immune system, and suggest that these isogenic murine models may prove a useful tool to study IDC in the absence of a non-obligatory DCIS stage-an under-investigated subset of poor prognostic human breast cancer.