Abstract P3-03-02: Identification of molecular pathways to define the intake rate of patient-derived hormone receptor positive (HR+) breast cancer xenografts (PDXs) in NOD/SCID/interleukin-2 receptor gamma chain null (NSG) mice
Authors: Kanaya N , Somlo G , Wu J , Frankel P , Wu SV , Nguyen D , Kai M , Chan N , Meng-Yin H , Kirschenbaum M , Kruper L , Vito C , Yuan Y , Hurria A , Mortimer J , Chen S 
Published: May 2016

Background and Purpose: Despite recent progress in our endocrine therapy of hormone receptor positive (HR+) breast cancers, a significant number of patients with primary breast cancer continue to relapse, and those with stage IV disease face a median overall survival of ∼ 3.5 years. Primary or acquired resistance to anti-estrogen-based therapies is an overarching challenge. To guide our treatment selection, there is an essential need to improve our understanding of the biology of HR+ breast tumors responsive to and those resist to anti-estrogens or aromatase inhibitors (AIs). The application of patient-derived xenografts (PDXs) in preclinical studies has begun to open the door to mimicking human disease on the research bench. However, HR+ breast cancer PDXs are difficult to establish. Although preclinical data from DeRose et al [Nat. Med. 2011: 17:1514-1520] indicate that the rate of engraftment serves as an independent predictor for poor outcome, the question which has not yet been adequately addressed is: "why some tumors can grow in mice, and some don't, even when their clinical, pathological stage and subtype (i.e. ER positivity) are same?" Here, we hypothesize that the molecular characteristics of patient HR+ tumors are key determinants to the tumor intake rate in NOD/SCID/interleukin-2 receptor gamma chain null (NSG) mice. Hence, reverse phase protein array (RPPA) analysis has be performed using human patient tumors to identify driver-pathways that impact tumor intake in NSG mice.

Results and Discussion: We compared the protein expression profile of six HR+ patient tumors (four HR+ and two HR+ HER2+), which were successfully engrafted into NSG mice and established as PDX models, with the patient tumors which we were unable to establish as PDX. Of 90 patient HR+ tumors which failed to transplant, 21 tumors were picked to match the tumor type (all of them were invasive ductal carcinoma or its metastases), clinical stage and pathological grade of engrafted tumors [Table 1]. In addition to patient tumors, six established HR+ PDXs were also submitted for analysis. Quantified expressions of 272 cancer-related proteins and phospho-proteins by RPPA have been performed on these specimens. Pathways identified as predictors of intake rate of PDXs in NSG mice, and tissues from paired PDX from mice with different passages, will be evaluated for the protein expression changes to elucidate the passage effects and generate therapeutic models based on protein expression and tumor growth.

Table 1. Characteristics of the patient tumors which were successfully established as PDX modelsERPgRHER2AgePatient ethnicityClinical stageNottingham histologic scoreSource++-63Hispanic3IIIBreast tumor+--71Hispanic2IIIBreast tumor+--52African-american4N/ABrain mets+--63Caucasian4N/AChest wall mets+-+34Caucasian2IIBreast tumor+++72Caucasian4IIIChest wall metsmets: metastases

Citation Format: Kanaya N, Somlo G, Wu J, Frankel P, Wu SV, Nguyen D, Kai M, Chan N, Meng-Yin H, Kirschenbaum M, Kruper L, Vito C, Yuan Y, Hurria A, Mortimer J, Chen S. Identification of molecular pathways to define the intake rate of patient-derived hormone receptor positive (HR+) breast cancer xenografts (PDXs) in NOD/SCID/interleukin-2 receptor gamma chain null (NSG) mice. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-03-02.