Abstract 6082: TP53-GATA3 mutation status predisposes luminal-to-basal subtype conversion in advanced breast cancer patients
Authors: Ryu Won-Ji , Kim Hyun-Yi , Kim Tae Yeong , Choi Yeona , Hahn Hyun Ju , Kim Seul-Gi , Kim Gun Min , Koo Ja Seung , Kim Seung Il , Sohn Joohyuk , Kim Min Hwan 
Published: June 2022

Background The molecular selective pressure on anti-tumor therapy drives lineage plasticity in several cancer types to develop drug resistance. The subtype conversion from luminal to triple-negative breast cancer (TNBC) subtype fuels endocrine resistance and disease aggressiveness. In this study, we analyzed mechanisms of luminal to basal subtype conversion by clinical sample sequencing and molecular study.

Method We performed whole-exome sequencing (WES) of primary and metastatic tumor tissues from breast cancer patients with luminal to basal [from HR(+)/HER2(-) to TNBC] subtype conversion (experimental, n=14) and patients with subtype maintenance (luminal to luminal subtype, control, n= 36) after adjuvant endocrine therapy. For RNA-sequencing, the subset of patients (experimental, n=14; control n=7) was further analyzed. The differences in genetic alterations and gene expression were compared between two patient groups to identify genetic predictors of subtype conversion. We also manipulated genetic factors related to subtype conversion in MCF7 cells to identify molecular signaling to drive lineage change.

Results In WES analysis, TP53 mutation was more frequently observed in luminal breast cancer patients with subtype conversion to TNBC [60% (12 out of 20 tissues in experimental group) versus 20% (8/40 tissues in control group)]. Whereas, GATA3 mutations were only observed in patients of subtype maintenance (0% versus 20%), and the mRNA level of GATA3 was downregulated after luminal-to-basal conversion. The TP53 and GATA3 mutations were both observed in the matched primary and metastatic tissues, suggesting that these mutations predisposed subtype conversion but were not acquired during the adjuvant endocrine therapy. In expression signature analysis, the patients with subtype conversion showed the upregulation of KRAS signaling and the suppression of GATA3 signature in metastatic TNBC tumors compared to primary luminal tumors. In primary tumors, RELA and MYC signatures were only upregulated in tumors that underwent subtype conversion later. We found ESR1 expression was decreased by knockdown of TP53 and GATA3 in MCF7 cells. The knockdown of TP53 and GATA3 also induced basal marker expressions, cytokeratin 5 and 14, in MCF7 cells. ESR1 expression and luminal markers were also decreased by GATA3 suppression in T47D harboring TP53 mutation.

Conclusion In luminal-type breast cancer, the subtype conversion is the one of the major obstacles for their treatment and preventing recurrence. We found the genetic alterations of TP53 mutation was the key predisposing factor of luminal to basal subtype conversion, whereas GATA3 mutation is a protecting factor for subtype conversion in luminal breast cancers. Thus, targeting TP53-GATA3 axis would be a potential therapeutic strategy to overcome endocrine resistance and block the subtype conversion in luminal type breast cancer.

Citation Format: Won-Ji Ryu, Hyun-Yi Kim, Tae Yeong Kim, Yeona Choi, Hyun Ju Hahn, Seul-Gi Kim, Gun Min Kim, Ja Seung Koo, Seung Il Kim, Joohyuk Sohn, Min Hwan Kim. TP53-GATA3 mutation status predisposes luminal-to-basal subtype conversion in advanced breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6082.