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Updated: Aug 9, 2025
Clinicopathological Analysis of miRNA Expression in Breast Cancer Tissues by Using miRNA In Situ Hybridization
Published on: June 7, 2016
Cell State Transitions and Phenotypic Heterogeneity in Luminal Breast Cancer Implicating MicroRNAs as Potential
Vinitha Richard1, Madhumathy G Nair2, Vishnu S Jaikumar3
1Discipline of Surgery, Lambe Institute for Translational Research, University of Galway, H91 V4AY Galway, Ireland.
Abstract:
Luminal breast cancer subtypes respond poorly to endocrine and trastuzumab treatments due to cellular heterogeneity arising from the phenotype transitions, accounted for mainly by the loss of receptor expression. The origins of basal-like and human epidermal growth factor receptor 2 (HER2)-overexpressing breast cancer subtypes have been attributed to genetic and protein modifications in stem-like cells and luminal progenitor cell populations, respectively. The post-transcriptional regulation of protein expression is known to be influenced by microRNAs (miRNAs) that are deemed to be master regulators of several biological processes in breast tumorigenesis and progression. Our objective was to identify the fractions of luminal breast cancer cells that share stemness potentials and marker profiles and to elucidate the molecular regulatory mechanism that drives transitions between fractions, leading to receptor discordances. Established breast cancer cell lines of all prominent subtypes were screened for the expression of putative cancer stem cell (CSC) markers and drug transporter proteins using a side population (SP) assay. Flow-cytometry-sorted fractions of luminal cancer cells implanted in immunocompromised mice generated a pre-clinical estrogen receptor alpha (ERα+) animal model with multiple tumorigenic fractions displaying differential expression of drug transporters and hormone receptors. Despite an abundance of estrogen receptor 1 (ESR1) gene transcripts, few fractions transitioned to the triple-negative breast cancer (TNBC) phenotype with a visible loss of ER protein expression and a distinct microRNA expression profile that is reportedly enriched in breast CSCs. The translation of this study has the potential to provide novel therapeutic miRNA-based targets to counter the dreaded subtype transitions and the failure of antihormonal therapies in the luminal breast cancer subtype.
Insights
Luminal breast cancer cells can transition to aggressive subtypes, losing hormone receptor expression. MicroRNAs (miRNAs) drive these transitions, offering potential therapeutic targets for endocrine therapy resistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Luminal breast cancer's poor response to treatment stems from cellular heterogeneity and phenotype transitions, often involving receptor loss.
- Subtypes like basal-like and HER2-overexpressing breast cancer originate from stem-like and luminal progenitor cells, respectively.
- MicroRNAs (miRNAs) are key post-transcriptional regulators in breast cancer development and progression.
Purpose of the Study:
- To identify luminal breast cancer cell fractions with stemness potential and shared markers.
- To understand the molecular mechanisms driving transitions between these fractions, causing receptor discordance.
- To explore miRNA's role in luminal breast cancer subtype transitions.
Main Methods:
- Screening of established breast cancer cell lines for cancer stem cell (CSC) markers and drug transporters using a side population (SP) assay.
- Implantation of flow-cytometry-sorted luminal cancer cell fractions into immunocompromised mice to create a preclinical model.
- Analysis of gene and protein expression, including estrogen receptor (ER) and microRNA profiles.
Main Results:
- Preclinical models revealed multiple tumorigenic fractions with differential expression of drug transporters and hormone receptors.
- Despite high estrogen receptor 1 (ESR1) transcripts, some fractions transitioned to triple-negative breast cancer (TNBC) phenotype with ER protein loss.
- These transitioning fractions exhibited distinct miRNA profiles associated with breast CSCs.
Conclusions:
- Cellular heterogeneity and phenotype plasticity contribute to treatment resistance in luminal breast cancer.
- MicroRNAs play a critical role in driving transitions to more aggressive subtypes and loss of hormone receptor expression.
- Targeting specific miRNAs may offer novel therapeutic strategies to overcome endocrine therapy resistance in luminal breast cancer.
