A Novel Animal Model for Locally Advanced Breast Cancer

Abstract

Background Locally advanced breast cancer (LABC) poses complex management issues due to failure of response to chemotherapy and progression to local complications such as skin erosion, superinfection and lymphedema. Most cell line and animal models are not adequate to study LABC. Methods A patient-derived xenograft (IOWA-1T) from a patient with LABC was characterized for expression profile, short tandem repeat (STR) profile, oncogenic mutations, xenograft growth and response to therapy. Results STR profile authenticated the cell line as derived from a human female. The primary tumor and derived xenografts were weakly ERα-positive (<5%), PgR-negative and HER2 non-amplified. Expression array profile compared to MCF-7 and BT-549 cell lines indicate that IOWA-1T was more closely related to basal breast cancer. IOWA-1T harbors a homozygous R248Q mutation of the TP53 gene and in vitro invasion assay was comparable to BT-549, and greater than MCF-7. IOWA-1T xenografts developed palpable tumors in 9.6±1.6 days, compared to 49±13 days for parallel experiments with BT-20 cells (p<0.002). Tumor xenografts became locally advanced, growing to >2 cm in 21.6±2 days characterized by skin erosion necessitating euthanasia. The SUMO inhibitor anacardic acid inhibited the outgrowth of IOWA-1T xenografts, while doxorubicin had no effect on tumorigenesis. Conclusions IOWA-1T is a novel cell line with an expression pattern consistent with basal breast cancer. Xenografts recapitulated LABC and provide a novel model for testing therapeutic drugs that may be effective in cases resistant to conventional chemotherapy.

Inhibiting the SUMO Pathway Represses the Cancer Stem Cell Population in Breast and Colorectal Carcinomas

“…Previous tumorigenesis studies demonstrated a significant effect of SUMO inhibitors to repress the outgrowth of basal breast cancer xenografts (Bogachek et al., 2014, Bogachek et al., 2015b). However, we noticed that after 1 month approximately 40% of the mice treated with anacardic acid developed small xenografts and we hypothesized that this was possibly due to outgrowth of non-CSC.…”

“…IOWA-1T was derived as described by Bogachek et al., 2015a, Bogachek et al., 2015b and is available through the ATCC. MDA-MB-436 and HCT116 were obtained from the ATCC.…”

“…We recently reported that sumoylation of transcription factor activator protein 2α (TFAP2A) in basal breast cancer alters its transcriptional activity and that SUMO-unconjugated TFAP2A acquires activity that results in a profound alteration of the expression profile away from the CSC/EMT phenotype and toward that of the well-differentiated phenotype, clearing of the CD44 +/hi /CD24 −/low CSC population, and repressing the TIC potential (Bogachek et al., 2014). Treatment of mice with anacardic acid inhibited the outgrowth of basal breast cancer xenografts, demonstrating the proof of principle that small-molecule SUMO inhibitors might form the basis of CSC-specific therapy (Bogachek et al., 2014, Bogachek et al., 2015b). Another recent study reported that knockdown of the SUMO enzyme PIAS1 repressed the TIC breast cancer population through epigenetic chromatin alterations resulting in gene silencing of cyclin D2, estrogen receptor, and WNT5A (Liu et al., 2014).…”

Towards the first targeted therapy for triple-negative breast cancer: Repositioning of clofazimine as a chemotherapy-compatible selective Wnt pathway inhibitor

“…These data, taken together with the well-established safety profile of clofazimine, prompted us to confirm its activity using in vivo models. We chose BT-20 as a somatic cancer cell line with a proven track of Wnt-dependent growth [24,59], and the IOWA-1T line corresponding to the chemoresistant cancer progenitor population [29], which has also been described to have and depend on high levels of Wnt signaling [60,61]. The second line was also our obvious choice for combination treatment, since it is particularly relevant for chemoresisitant tumors.…”

Establishment and characterization of three stable Basal/HER2-positive breast cancer cell lines derived from Chinese breast carcinoma with identical missense mutations in the DNA-binding domain of TP53

“…Basal/HER2+ breast cancer shows poorer survival than other phenotypes [ 29 , 30 ]. We examined the expression of HER2, along with luminal (PR, ER-α, keratin 18, FOXA1/HNF3α, and AGR2) [ 31 ], basal (EGFR, SPARC, Vimentin, and caveolin1–2), pluripotent (CD44 [ 32 ], and Stat3α/β, OCT-4, SOX2, and Nanog [ 33 , 34 ]) and prognosis (CD146 and VDR) markers by western blotting. CD146 [ 35 ], and VDR [ 36 , 37 ] are associated with poor and excellent prognosis, respectively.…”