TY - JOUR
T1 - Isogenic Mammary Models of Intraductal Carcinoma Reveal Progression to Invasiveness in the Absence of a Non-Obligatory In Situ Stage
AU - Bernhardt, Sarah M.
AU - Mitchell, Elizabeth
AU - Stamnes, Stephanie
AU - Hoffmann, Reuben J.
AU - Calhoun, Andrea
AU - Klug, Alex
AU - Russell, Tanya D.
AU - Pennock, Nathan D.
AU - Walker, Joshua
AU - Schedin, Pepper
N1 - Publisher Copyright:
© 2023 by the authors.
PY - 2023/4
Y1 - 2023/4
N2 - 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, α-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.
AB - 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, α-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.
KW - ductal carcinoma in situ
KW - immune-competent
KW - mouse-intraductal (MIND) model
KW - myoepithelium
KW - pure invasive ductal carcinoma
UR - http://www.scopus.com/inward/record.url?scp=85153962586&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85153962586&partnerID=8YFLogxK
U2 - 10.3390/cancers15082257
DO - 10.3390/cancers15082257
M3 - Article
AN - SCOPUS:85153962586
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 8
M1 - 2257
ER -