Abstract LB-140: Myoepithelial-immune cell crosstalk in the transition from non-invasive to invasive breast cancer
Authors: Mitchell Elizabeth , Jindal Sonali , Chan Tiffany , Narasimhan Jayasri , Weinmann Sheila , Schedin Pepper 
Published: August 2019

The incidence of ductal carcinoma in situ (DCIS), a pre-invasive malignancy of the breast, has increased in the U.S. since the 1980s, from 3% to 20% of all breast cancer diagnoses. This increase is largely attributed to mammographic screening. Common treatments of DCIS are breast-conserving surgery followed by adjuvant radiation therapy or mastectomy. Further, despite efforts to detect and treat early stage cancer, the incidence of invasive breast cancer (IBC) has not declined, suggesting that many women with DCIS are over treated. Thus, prognostic markers that predict risk of DCIS progression are needed. Genomic studies have yet to find tumor intrinsic alterations that predict DCIS progression to IBC. In contrast, genetic changes in the myoepithelium are found at the transition from DCIS to IBC, suggesting myoepithelial cells may play a role in progression. To investigate the myoepithelium for potential biomarkers, we advanced a non-surgical intraductal tumor cell delivery model in mice using human DCIS.com cells. We reported a progressive loss in myoepithelial differentiation markers p63, calponin, and smooth muscle actin (SMA) prior to transition to IBC, observations that were confirmed in human DCIS. Thus, compromise in the myoepithelium may be an early warning for DCIS at high risk for progression. Here, we hypothesize that the myoepithelial differentiation state informs immune response, and that DCIS lesions with loss of myoepithelial Calponin and SMA will be associated with a pro-tumorigenic immune milieu. This hypothesis is based on observations by us and others showing lymphocyte infiltration in areas where the DCIS myoepithelium has been focally compromised. To address this, we analyzed the expression of 10 myoepithelial and lymphoid biomarkers using multiplex immunohistochemistry to analyze the relationship between myoepithelial cell integrity and immune cells (N=36 cases). DCIS in the background of IBC (mixed DCIS) is assumed to be high-risk DCIS. We find compromised myoepithelial calponin in mixed compared to pure DCIS. Mixed lesions also show reduced infiltration of immune and T-cells, consistent with reduced immune surveillance. However, calponin loss in pure DCIS cases was associated with a decrease in Foxp3+ T-regulatory cells and increase in CD8+PD-1+ T-cells. Next we found that DCIS areas with focal loss of the myoepithelium and micro-invasion showed an increase in immune infiltration, increased T-cells, and increased PD-1+CD8+ T-cells. These data suggest that early compromise in the myoepithelial layer may associate with activation of cytotoxic effectors, consistent with increased immune surveillance. However, since we find T-cell numbers are reduced in mixed DCIS, effective immune surveillance may be dampened with progression. These data support an unreported relationship between myoepithelial cell integrity and the activation state of local immune cells.

Citation Format: Elizabeth Mitchell, Sonali Jindal, Tiffany Chan, Jayasri Narasimhan, Sheila Weinmann, Pepper Schedin. Myoepithelial-immune cell crosstalk in the transition from non-invasive to invasive breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-140.