# ERα36 Promotes MDR1-Mediated Adriamycin Resistance via Non-Genomic Signaling in Triple-Negative Breast Cancer

## TL;DR

This study shows that ERα36 helps breast cancer cells resist chemotherapy by boosting MDR1 through non-genomic signaling, offering a new target for treatment.

## Contribution

The paper reveals a novel non-genomic mechanism by which ERα36 promotes Adriamycin resistance via MDR1 upregulation in triple-negative breast cancer.

## Key findings

- ERα36 activation increases MDR1 expression and drug resistance in breast cancer cells.
- ERα36 activates Akt/ERK-NF-κB/CREB and Wnt/β-catenin pathways to upregulate MDR1.
- Silencing ERα36 reduces MDR1 expression and drug resistance.

## Abstract

Drug resistance remains a critical barrier to effective treatment in several cancers, particularly triple-negative breast cancer (TNBC). Estrogen receptor α36 (ERα36), a variant of the estrogen receptor in ER-negative breast cancer cells, plays important roles in cancer cell proliferation. We investigated the role of ERα36 in regulating multidrug resistance protein 1 (MDR1) in MDA-MB-231 human breast cancer cells. The activation of ERα36 by BSA-conjugated estradiol (BSA-E2) increased cell viability under Adriamycin exposure, suggesting its involvement in promoting drug resistance. BSA-E2 treatment significantly reduced the intracellular rhodamine-123 levels by activating the MDR1 efflux function, which was linked to increased MDR1 transcription and protein expression. The mechanical ERα36-mediated BSA-E2-induced activation of EGFR and downstream signaling via c-Src led to an activation of the Akt/ERK pathways and transcription factors, NF-κB and CREB. Additionally, ERα36 is involved in activating Wnt/β-catenin pathways to induce MDR1 expression. The silencing of ERα36 inhibited the BSA-E2-induced phosphorylation of Akt and ERK, thereby reducing MDR1 expression via downregulation of NF-κB and CREB as well as Wnt/β-catenin signaling. These findings demonstrated that ERα36 promotes MDR1 expression through multiple non-genomic signaling cascades, including Akt/ERK-NF-κB/CREB and Wnt/β-catenin pathways, and highlight the role of ERα36 as a promising target to enhance chemotherapeutic efficacy in TNBC.