Abstract P3-04-26: Establishment and characterization of ST941/C; an ESR1-mutant ER+ breast cancer cell line and xenograft from a patient with acquired resistance to endocrine therapy
Authors: Wick MJ , Diaz A , Thomas M , Moriarty A , Quinn M , Guerra M , Zhu P , Smith P , Tolcher AW , Puyang X , Patnaik A , Korpal M , Rasco D , Papadopoulos KP 
Published: March 2017

Background: The estrogen receptor (ERα) plays an integral role in the progression of luminal type breast cancers and while targeted endocrine therapies provide effective initial treatment many patients develop acquired resistance to treatment even with continued ER receptor expression. Recently studies identified ER mutations as a possible mechanism for acquired resistance and several activating point mutations have been identified including Y537S (ESR1Y537S) resulting in hormone independent proliferation in preclinical studies. However, lack of validated ESR1-mutant cell lines has limited detailed mechanistic studies of these mutations in endocrine-resistant ER+ breast cancer. Previously we established and evaluated a patient derived xenograft (PDX) designated ST941 representing ESR1Y537S-mutated ER+ breast cancer (Wick et al, SABCS 2015). To better understand the role of ESR1-mutations in endocrine resistant breast cancer we established an immortalized cell line from ST941 designated ST941/C to use for in vitro mechanistic assays and correlative in vivo studies.

Methods: The ST941/C cell line was generated from harvested low-passage ST941 PDX tissue using published methods. Once established the line was characterized by immunohistochemistry and NGS and its tumorigenicity assessed. Drug sensitivity studies were carried out evaluating relevant endocrine and chemotherapy agents and results compared with in vivo drug studies. Timepoints for cell proliferation assays were Days 4, 7 and 10 following cell plating using standard MTS assay. Endpoints for in vivo studies were a mean group tumor volume of ~1 cm3 or sixty days following treatment initiation.

Results: Subcutaneous cell injection into athymic nude mice produced xenografts which grew in the absence of exogenous hormone. The ST941/C cell line and resulting xenograft retained immunohistologic and NGS characteristics of the parent model including receptor expression and ER mutation. Both the cell line and xenograft were insensitive to most endocrine therapies including tamoxifen, fulvestrant and aromatase inhibitors and reported correlative activity towards docetaxel and other chemotherapies.

Conclusion: We have established and evaluated an ESR1-mutant cell line designated ST941/C which is tumorigenic in nude mice and potentially useful for mechanistic and correlative in vivo studies to better understand acquired resistance in endocrine-treated ER+ breast cancer.

Citation Format: Wick MJ, Diaz A, Thomas M, Moriarty A, Quinn M, Guerra M, Zhu P, Smith P, Tolcher AW, Puyang X, Patnaik A, Korpal M, Rasco D, Papadopoulos KP. Establishment and characterization of ST941/C; an ESR1-mutant ER+ breast cancer cell line and xenograft from a patient with acquired resistance to endocrine therapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P3-04-26.