Dataset Information

SERPINA3-ANKRD11-HDAC3 pathway induced aromatase inhibitor resistance in breast cancer can be reversed by HDAC3 inhibition.

ABSTRACT: Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and found 7 commonly dysregulated genes in endocrine-resistant breast cancer cells. Here we show that downregulation of serine protease inhibitor clade A member 3 (SERPINA3) which is a direct target gene of estrogen receptor α contributes to aromatase inhibitor resistance. Ankyrin repeat domain containing 11 (ANKRD11) works as a downstream effector of SERPINA3 in mediating endocrine-resistance. It induces aromatase inhibitor insensitivity by interacting with histone deacetylase 3 (HDAC3) and upregulating its activity. Our study suggests that aromatase inhibitor therapy downregulates SERPINA3 and leads to the ensuing upregulation of ANKRD11, which in turn promotes aromatase inhibitor resistance via binding to and activating HDAC3. HDAC3 inhibition may reverse the aromatase inhibitor resistance in ER-positive breast cancer with decreased SERPINA3 and increased ANKRD11 expression.

SUBMITTER: Zhou J

PROVIDER: S-EPMC10326080 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

SERPINA3-ANKRD11-HDAC3 pathway induced aromatase inhibitor resistance in breast cancer can be reversed by HDAC3 inhibition.

Zhou Jing J Zhu Mengdi M Wang Qi Q Deng Yiyuan Y Liu Nianqiu N Liu Yujie Y Liu Qiang Q

Communications biology 20230706 1

Endocrine resistance is a major challenge for breast cancer therapy. To identify the genes pivotal for endocrine-resistance progression, we screened five datasets and found 7 commonly dysregulated genes in endocrine-resistant breast cancer cells. Here we show that downregulation of serine protease inhibitor clade A member 3 (SERPINA3) which is a direct target gene of estrogen receptor α contributes to aromatase inhibitor resistance. Ankyrin repeat domain containing 11 (ANKRD11) works as a downst ...[more]

PMID: 37414914

Similar Datasets

Project description:BackgroundSelection of resistance mutations may play a major role in the development of endocrine resistance. ESR1 mutations are rare in primary breast cancer but have high prevalence in patients treated with aromatase inhibitors (AI) for advanced breast cancer. We investigated the evolution of genetic resistance to the first-line AI therapy using sequential ctDNA sampling in patients with advanced breast cancer.Patients and methodsEighty-three patients on the first-line AI therapy for metastatic breast cancer were enrolled in a prospective study. Plasma samples were collected every 3 months to disease progression and ctDNA analysed by digital droplet PCR and enhanced tagged-amplicon sequencing (eTAm-Seq). Mutations identified in progression samples by sequencing were tracked back through samples before progression to study the evolution of mutations on therapy. The frequency of novel mutations was validated in an independent cohort of available baseline plasma samples in the Study of Faslodex versus Exemestane with or without Arimidex (SoFEA) trial, which enrolled patients with prior sensitivity to AI.ResultsOf the 39 patients who progressed on the first-line AI, 56.4% (22/39) had ESR1 mutations detectable at progression, which were polyclonal in 40.9% (9/22) patients. In serial tracking, ESR1 mutations were detectable median 6.7 months (95% confidence interval 3.7-NA) before clinical progression. Utilising eTAm-Seq ctDNA sequencing of progression plasma, ESR1 mutations were demonstrated to be sub-clonal in 72.2% (13/18) patients. Mutations in RAS genes were identified in 15.4% (6/39) of progressing patients (4 KRAS, 1 HRAS, 1 NRAS). In SoFEA, KRAS mutations were detected in 21.2% (24/113) patients although there was no evidence that KRAS mutation status was prognostic for progression free or overall survival.ConclusionsCancers progressing on the first-line AI show high levels of genetic heterogeneity, with frequent sub-clonal mutations. Sub-clonal KRAS mutations are found at high frequency. The genetic diversity of AI resistant cancers may limit subsequent targeted therapy approaches.

Dataset Information

SERPINA3-ANKRD11-HDAC3 pathway induced aromatase inhibitor resistance in breast cancer can be reversed by HDAC3 inhibition.

Publications

SERPINA3-ANKRD11-HDAC3 pathway induced aromatase inhibitor resistance in breast cancer can be reversed by HDAC3 inhibition.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets