The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response

Sep 24, 2026

Breast cancer is the second leading cause of cancer-related death in women worldwide, and its treatment relies on surgery, radiation, chemotherapy, and immunotherapy, with effectiveness shaped by molecular subtype. Distinct alterations in sphingolipid metabolism—covering ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, along with biosynthetic and catabolic enzymes—emerge as molecular drivers of tumor growth, therapeutic response, and escape. By integrating dysregulated metabolites, enzymes, transport proteins, and sphingolipid-driven resistance mechanisms, the review highlights opportunities for diagnostic and prognostic biomarkers, aiming to improve personalization and reduce drug resistance.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages25

Reading Time1 h 3 min

AccessFree to download

Introduction

Breast cancer subtypes and biomarker-based classification

Therapeutic responses and limits due to resistance

Abstract

Role of sphingolipid metabolism in progression and drug response

Keywords

Core topics: sphingolipids, metabolism, ceramide and biomarkers

Review The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response Paola Antonia Corsetto , Stefania Zava, Angela Maria Rizzo * and Irma Colombo Citation: Corsetto, P.A.; Zava, S.; Rizzo, A.M.; Colombo, I. The Critical Impact of Sphingolipid Metabolism in Breast Cancer Progression and Drug Response. Int. J. Mol. Sci. 2023, 24, 2107. [https://doi.org/10.3390/](https://doi.org/10.3390/)[ ](https://doi.org/10.3390/)ijms24032107 Academic Editor: Bernard Haendler Received: 13 December 2022 Revised: 11 January 2023 Accepted: 17 January 2023 Published: 20 January 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) . Department of Pharmacological and Biomolecular Sciences, Universit degli Studi di Milano, Via D. Trentacoste 2, 20134 Milano, Italy * Correspondence: [angelamaria.rizzo@unimi.it](angelamaria.rizzo@unimi.it); Tel.: +39-02-5031-5777 Abstract: Breast cancer is the second leading cause of cancer-related death in women in the world, and its management includes a combination of surgery, radiation therapy, chemotherapy, and immunotherapy, whose effectiveness depends largely, but not exclusively, on the molecular subtype (Luminal A, Luminal B, HER2+ and Triple Negative) . All breast cancer subtypes are accompanied by peculiar and substantial changes in sphingolipid metabolism. Alterations in sphingolipid metabolite levels, such as ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, as well as in their biosynthetic and catabolic enzymatic pathways, have emerged as molecular mechanisms by which breast cancer cells grow, respond to or escape therapeutic interventions and could take on diagnostic and prognostic value. In this review, we summarize the current landscape around two main themes: 1 . sphingolipid metabolites, enzymes and transport proteins that have been found dysregulated in human breast cancer cells and/or tissues; 2 . sphingolipid-driven mechanisms that allow breast cancer cells to respond to or evade therapies. Having a complete picture of the impact of the sphingolipid metabolism in the development and progression of breast cancer may provide an effective means to improve and personalize treatments and reduce associated drug resistance. Keywords: breast cancer; sphingolipids; lipids; metabolism; ceramide; sphingomyelin; drug sensitivity; drug resistance; biomarkers 1. Introduction Breast cancer (BC) continues to be the second leading cause of cancer death among women worldwide, despite, over the last 30 years, BC death rates dropping due to increased awareness of the disease, advances in diagnosis, and more effective therapeutic interventions [1] . Major advances regarding diagnosis, prognosis, and treatment of BC, including in surgery, chemotherapy, immunotherapy, and radiotherapy, are due to multiple and interdisciplinary approaches which, over time, have led to a progressive improvement in the classiﬁcation of BCs [2–5] . Currently, the classiﬁcation system of BCs considered most useful and effective, and therefore increasingly used by clinicians for the choice of therapeutic intervention, is based on the presence, or absence, of speciﬁc biomarkers in tumor specimens [3,6] . In particular, according to estrogen receptor (ER) and progesterone receptor (PR) expression levels and human epidermal growth factor receptor 2 (ErbB2, also known as HER2) status, BCs are basically divided into four main subtypes [3,6] . Luminal A and Luminal B BCs are both positive for hormone receptors (ER+ and PR+) but differ in the HER2 status (Luminal A is HER2-, whereas Luminal B is HER2+) and in the expression levels of the cell diffe

FAQs

What treatments are discussed for managing breast cancer, and what determines their effectiveness?

Management combines surgery, radiation therapy, chemotherapy, and immunotherapy. Effectiveness depends largely, though not exclusively, on the breast cancer molecular subtype.

Which sphingolipid molecules and metabolic changes are linked to breast cancer progression and therapy response?

The review highlights alterations in sphingolipid metabolite levels such as ceramides, dihydroceramide, sphingosine, sphingosine-1-phosphate, and sphingomyelin, plus changes in their biosynthetic and catabolic enzymatic pathways.

How do sphingolipids relate to drug response and drug resistance in breast cancer?

Sphingolipid-driven mechanisms can help cancer cells respond to or evade therapies, and a complete understanding of sphingolipid metabolism may support improved personalization and reduced drug resistance.

Sep 24, 2026

Uploaded by anakgang17