THU477 Drivers Of Estrogen Induced Invasive Lobular Carcinoma

Abstract Disclosure: C. Ufondu: None. L. Clem: None. M. Musick: None. M.J. Sikora: None. J.H. Ostrander: None. Invasive lobular carcinoma (ILC) is an estrogen-receptor (ER)-positive histologic subtype of breast cancer typically treated with anti-estrogens (i.e., tamoxifen and aromatase inhibitors). Anti-estrogen resistance and disease progression occur in about 34% of patients with ILC, but mechanisms of resistance have been underexplored. Additionally, estrogen-only hormone replacement therapy increases the risk of ILC, but not the more common invasive ductal carcinoma (IDC), highlighting a potentially unique role for estrogen in ILC initiation and progression. To identify mediators of estrogen-induced ILC progression we are using the the mouse mammary intraductal (MIND) model, which better recapitulates the progression of ILC and response to estrogen in vivo. MM134, MM330, and SUM44PE ILC cell lines were injected intraductally into the #4 mammary glands of NSG mice. Mice were monitored for up to 20 weeks with or without estrogen supplemented in the drinking water. Our results show that MIND supports an in situ-like to invasive disease progression for ILC cell lines, and that estrogen accelerated tumor growth and invasion in vivo. Current studies are aimed at identifying mediators that drive estrogen-induced tumor growth and invasion in vivo, focusing on E-cadherin (CDH1) loss as the genetic hallmark of ILC occurring in ∼95% of cases. We aim to identify how loss of E-cadherin in normal human mammary epithelial cells (HMECs) may lead to reprogramming of ER and promote the development of ILC. We are developing a CRISPR/Cas9 approach for knocking out CDH1 in HMECs. We will study estrogen response in the CDH1-knockout versus control HMECs in vitro to examine whether loss contributes to ILC-specific estrogen activity. Using the MIND model, we will engraft the control and knockout cells into the ducts of adult female NSG mice and monitor tumor growth through bioluminescence imaging. ER reprogramming will be assessed in the engrafted cells using RNAseq and CUT&RUN (Cleavage Under Target & Release Using Nuclease). We predict that E-cadherin loss will reprogram ER DNA binding, dysregulate transcription factors linked to E-cadherin, such as TCF/LEF, and confirm critical downstream regulators that mediate estrogen-driven tumorigenesis. Understanding the unique contributions of ER in ILC could lead to new therapeutic strategies for the prevention and treatment of ILC. Presentation: Thursday, June 15, 2023