Abstract B29: A novel mammary intraductal delivery model that permits study of human ductal carcinoma in situ progression.
Authors: Russell Tanya D. , Agunbiade Samiat , Jindal Sonali , Fornetti Jaime , Borges Virginia , Schedin Pepper 
Published: August 2014

Young African American women have an increased risk of developing aggressive forms of breast cancer (i.e. triple negative/basal-like) than young non-Hispanic white women. Recent epidemiological data show increased risk of basal-like breast cancer with increased childbearing in African American women (Millikan et al 2008; Palmer et al 2011). Breast cancers associated with a recent pregnancy (pregnancy-associated breast cancer) are more likely to be metastatic (Lyons et al 2011). We predict that the triple negative/basal-like breast cancer subtype is promoted by a recent pregnancy, accounting in part, for the poor prognosis of young African American breast cancer patients.

We have developed a murine intraductal mammary model to examine the effect of host reproductive status on the progression of early stage human breast cancer. Our model delivers human mammary tumor cells directly through the intact mouse teat into the correct anatomical location for ductal carcinoma in situ (DCIS) without surgical manipulations. MCF10ADCIS.com (triple negative/basal cell line) or HCC70 (triple negative cell line derived from a young African American woman) cells were delivered into the mammary gland via intraductal injection to assess influence of host reproductive state (nulliparity, pregnancy, active post-partum involution) on tumor progression.

Lesions from both cell lines displayed the full representation of human DCIS histologic subtypes, which progressed to DCIS through an atypical ductal hyperplasia stage. Although the MCF10ADCIS.com cell line is typically triple negative in vitro and other in vivo models, established tumors in the intraductal model were observed to re-express estrogen receptor. HCC70 tumors maintained the triple negative phenotype in our model. Using the MCF10ADCIS.com model to assess the effects of host reproductive status on DCIS progression, we found tumor burden in the pregnancy group was not significantly different than nulliparous controls. Within the pregnant group, tumors appear to be less proliferative and have slightly lower ER expression than nulliparous control tumors. Tumor burden in the postpartum involution group is significantly greater than the respective nulliparous control group; however, the Ki67 proliferative index is lower 4 weeks post injection in comparison to nulliparous controls. DCIS progression to locally invasive disease occurred with progressive loss of myoepithelial cell differentiation markers. In both cell line models, the loss of p63 was identified as an early indicator of compromised myoepithelium. Further, our data suggest that the protective myoepithelial cell layer may be preferentially compromised by tumors formed in postpartum involuting mammary glands.

Our murine mammary intraductal model of human breast cancer provides a rigorous approach to study early stage-tumor progression, and is well suited to study the effect of the host reproductive state on DCIS progression. Since occult tumors in women develop within ducts, we propose that this teat injection model will aid research of early disease progression, a requisite for research focused on breast cancer prevention and inhibition of local invasion. Further, this model may provide a unique opportunity to address and study tumor growth disparities among African American and non-Hispanic white women.

Citation Format: Tanya D. Russell, Samiat Agunbiade, Sonali Jindal, Jaime Fornetti, Virginia Borges, Pepper Schedin. A novel mammary intraductal delivery model that permits study of human ductal carcinoma in situ progression. [abstract]. In: Proceedings of the Fifth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2012 Oct 27-30; San Diego, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(10 Suppl):Abstract nr B29.