Association of miR-34a with metastatic progression through the FoxO3a–SIRT1 regulatory axis in breast cancer

TL;DR

This study explores how miR-34a, SIRT1, and FoxO3a interact to influence breast cancer metastasis, finding that miR-34a is lower in metastatic tumors.

Contribution

The study identifies a regulatory axis involving miR-34a, SIRT1, and FoxO3a in breast cancer metastasis.

Findings

miR-34a expression is significantly reduced in metastatic breast cancer tissues.

SIRT1 and FoxO3a levels are higher in metastatic tumors compared to nonmetastatic ones.

SIRT1 may act as a tumor promoter in metastatic settings through interactions with FoxO3a and miR-34a.

Abstract

Breast cancer represents the foremost cause of cancer-related mortality among women worldwide and is characterized by a markedly high metastatic potential, contributing substantially to its clinical severity and poor prognosis. This study aimed to evaluate the interrelationship among silent information regulator (SIRT1), Forkhead box O3a (FoxO3a), and microRNA-34a (miR-34a), the latter of which promotes apoptosis by suppressing the proliferation, migration, and invasion of breast cancer cells. Specifically, we investigated the tumor microenvironment associated with metastatic progression of malignant primary tumors, the influence of nonmetastatic (benign) tumors, and the potential roles of these proteins in both primary tumor development and metastasis.

In this study, metastatic 4TLM and nonmetastatic 67NR breast cancer cell lines were used. These cell lines were orthotopically injected into the mammary fat pads of 8–10-week-old female Bagg Albino laboratory-bred strain c (BALB/c) mice. Mice were sacrificed 28 days postinjection, and primary tumors, lungs, and liver tissues were collected for analysis. Expression levels of SIRT1, FoxO3a, and miR-34a were evaluated using immunohistochemistry, Western blotting, and RT-PCR.

Expression levels of SIRT1 and FoxO3a were significantly higher in metastatic 4TLM tumors compared to the nonmetastatic 67NR group. Conversely, miR-34a expression was markedly higher in nonmetastatic tumors, whereas its level was reduced in metastatic tissues (p < 0.05). In metastatic tissues, SIRT1 expression remained elevated, whereas FoxO3a and miR-34a levels were significantly reduced (p < 0.05).

SIRT1 may act as either a tumor suppressor or a tumor promoter, depending on cellular context, signaling pathways, and its specific molecular targets across cancer types. The elevated expression of SIRT1 in 67NR primary tumors suggests a tumor-suppressive role in nonmetastatic settings. However, the increased SIRT1 expression observed in metastatic regions indicates its potential role as a tumor promoter and modulator of the tumor microenvironment, possibly through FoxO3a and miR-34a signaling, thereby enhancing cellular proliferation and invasion.

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