Citations 2
Novel transplantable mouse cell line model recapitulates invasive lobular breast carcinoma (ILC) phenotype and immune microenvironment
Onkar, Sayali , Liu, Daisong, Seachrist, Darcie D. , Zou, Jian , Merkel, Christopher , Thale, Insa , Chang, Alexander Chih-Chieh , Klei, Linda R. , Chen, Jian, Weber-Bonk, Kristen L. , Rigatti, Laura, Workman, Creg J. , Oesterreich, Steffi , Seachrist, Darcie , Klei, Linda , Bonk, Kristen Weber , Ding, Kai , Savariau, Laura , Yates, Megan , Hooda, Jagmohan , Stabile, Laura , Lucas, Peter C , Ruth, Keri , Workman, Creg J , Lee, Adrian V , Vignali, Dario A A , Oesterreich, Steffi , Savariau, Laura , Lucas, Peter C. , Tseng, George , Lee, Adrian V.
No container title available | August 3, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Invasive lobular breast carcinoma (ILC) is the most common special histological subtype of breast cancer, which accounts for 10-15% of all cases. To study the phenotype characteristics, metastatic growth kinetic and immune microenvironment of ILC, we developed an orthotopically transplantable cell line model from the spontaneous mammary fat pad tumor of CDH1-PTEN dual knockout C57BL/6 mouse with Cre-loxP system, designated CPT6. CPT6 recapitulates single-file growth pattern of human ILC, with pleomorphic features and a high mitotic index. RNA sequencing together with whole exome sequencing reveals a luminal A subtype with targetable driver mutations such as Kras G12C. As a novel orthotopically transplantable ILC model in immune competent mice, CPT6 shows robust in vivo growth and metastatic rate, and has moderate immunogenicity which appears to be T-cell independent. We also profiled the immune microenvironment of CPT6, revealing a myeloid-rich environment with dominant M2-macrophage population, which is concordant with human ILC. In summary, this model recapitulates human ILC phenotype and represents a valuable preclinical platform for evaluating immunotherapy and other therapeutic strategies for invasive lobular breast carcinoma.
Breast cancer ovarian metastases show increased activity of GPCR pathways
Savariau, Laura , Qin, Ye, Shah, Osama Shiraz , Basudan, Ahmed , Merkel, Chris , Sisoudiya, Saumya D. , Sivakumar, Smruthy , Sokol, Ethan , McGinn, Olivia , Li, Zheqi , Liu, Tiantong , Tasdemir, Nilgun , Tallapaneni, Pooja , Oesterreich, Steffi , Shah, Osama , Basudan, Ahmed M , Coffman, Lan , Elishaev, Esther , Lucas, Peter C , Lee, Adrian V , Oesterreich, Steffi , Li, Zheqi , Savariau, Laura , Elishaev, Esther , Atkinson, Jennifer M. , Lucas, Peter C. , Lee, Adrian V.
No container title available | August 1, 2026 | Volume: No volume available | Issue: No issue available | Pages: No page available
Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.