Abstract C032: The impact of neoadjuvant endocrine therapy (NET) in ER+ breast cancer tumor microenvironment and metastasis
Authors: Chondronikola Anastasia Aristoteleia , Anastasiadou Dimitra , Zintiridou Aliona , Duran Camille L. , Barth Nicole , Karadal-Ferrena Burcu , Pereira-Zambalde Erika , Ariyan Lina , Shukla Suryansh , Karagiannis George S. , Entenberg David , Condeelis John S. , Oktay Maja H. 
Published: November 2024

Abstract
Breast cancer is the most common cancer in women worldwide and the second leading cause of death. The Estrogen Receptor positive (ER+) subtype constitutes approximately 80% of the yearly 250,000 breast cancer diagnoses in the US. Anti-estrogen endocrine therapy, administered either pre- or post-operatively, is the cornerstone treatment for all stages of breast cancer. Pre- operative or neoadjuvant endocrine therapy (NET) reduces pre-surgical tumor burden, improves surgical outcome, and provides prognostic information. Although the treatment often has a favorable initial response, about 20% of patients eventually develop resistance and recurrent disease, even decades after the primary diagnosis.We hypothesized that resistance in NET is mediated through pro-metastatic changes in the tumor microenvironment affecting either (i) dissemination machinery or (ii) cancer cell phenotype.The main mode of breast cancer hematogenous dissemination to distant sites is through intravasation portals called Tumor Microenvironment of Metastasis (TMEM) doorways. Each TMEM doorway consists of a tumor cell overexpressing the actin-regulatory protein MENA, a Tie2high/ VEGFAhigh macrophage and an endothelial cell, all in direct contact. TMEM doorway activity leads to vascular opening events, during which tumor cells located in areas around TMEM doorways intravasate and disseminate to secondary sites. Therefore, to investigate the impact of NET on cancer cell dissemination, we evaluated its effect on (i) TMEM doorway score (the number of TMEM doorways per tissue area), (ii) TMEM doorway opening, (iii) the number of circulating tumor cells and (iv) the number of disseminated tumor cells. We used the orthotopic MCF7 breast cancer xenograft model grown in NOD/SCID mice and tested two drugs widely used in NET, Fulvestrant (a Selective Estrogen Receptor Degrader) and Tamoxifen (a Selective Estrogen Receptor Modulator). NET did not affect the TMEM doorway score, TMEM doorway activity, the number of CTCs or the number of DTCs. We are now focused on evaluating the effect of NET on the density of cancer cells which are upregulated in programs of invasion, stemness, and dormancy. This “Triple Threat Phenotype (TTP)” gives tumor cells an enhanced ability to disseminate to and colonize distant organs. To this effect we will stain primary MCF7 tumors from NET and vehicle-treated mice for markers of invasiveness (MENA), stemness (SOX9) and dormancy (NR2F1). Detecting any changes in the phenotype of metastatic tumor cells following NET will help us understand underlying mechanisms of endocrine therapy resistance and may lead to new therapeutic targets and improve patient outcomes.
Citation Format: Anastasia Aristoteleia Chondronikola, Dimitra Anastasiadou, Aliona Zintiridou, Camille L. Duran, Nicole Barth, Burcu Karadal-Ferrena, Erika Pereira-Zambalde, Lina Ariyan, Suryansh Shukla, George S. Karagiannis, David Entenberg, John S. Condeelis, Maja H. Oktay. The impact of neoadjuvant endocrine therapy (NET) in ER+ breast cancer tumor microenvironment and metastasis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C032.