International Journal of Molecular Sciences

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23 pages, 3059 KiB

Open AccessArticle

Tamoxifen Activates Transcription Factor EB and Triggers Protective Autophagy in Breast Cancer Cells by Inducing Lysosomal Calcium Release: A Gateway to the Onset of Endocrine Resistance

by Cecilia Boretto, Chiara Actis, Pawan Faris, Francesca Cordero, Marco Beccuti, Giulio Ferrero, Giuliana Muzio, Francesco Moccia and Riccardo Autelli

Int. J. Mol. Sci. 2024, 25(1), 458; https://doi.org/10.3390/ijms25010458 - 29 Dec 2023

Cited by 1 | Viewed by 892

Abstract

Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal [...] Read more.

Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal biogenesis. However, the mechanisms by which this occurs have not been elucidated as yet. This investigation aims at dissecting how TFEB is activated and contributes to Tam resistance in luminal A breast cancer cells. TFEB was overexpressed and prominently nuclear in Tam-resistant MCF7 cells (MCF7-TamR) compared with their parental counterpart, and this was not dependent on alterations of its nucleo-cytoplasmic shuttling. Tam promoted the release of lysosomal Ca²⁺ through the major transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) and two-pore channels (TPCs), which caused the nuclear translocation and activation of TFEB. Consistently, inhibiting lysosomal calcium release restored the susceptibility of MCF7-TamR cells to Tam. Our findings demonstrate that Tam drives the nuclear relocation and transcriptional activation of TFEB by triggering the release of Ca²⁺ from the acidic compartment, and they suggest that lysosomal Ca²⁺ channels may represent new druggable targets to counteract the onset of autophagy-mediated endocrine resistance in luminal A breast cancer cells. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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12 pages, 866 KiB

Open AccessArticle

The Clinical Relevance of the NATALEE Study: Application of the NATALEE Criteria to a Real-World Cohort from Two Large German Breast Cancer Centers

by Henning Schäffler, Franziska Mergel, Kerstin Pfister, Stephan Lukac, Angelina Fink, Kristina Veselinovic, Brigitte Rack, Visnja Fink, Elena Leinert, Moritz Dimpfl, Alexander Englisch, Christian Martin Tegeler, Anna Seller, Eva-Maria Grischke, Markus Hahn, Léa Louise Volmer, Tobias Engler, Marie Louise Frevert, Florin Andrei Taran, Wolfgang Janni, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Dominik Dannehl Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(22), 16366; https://doi.org/10.3390/ijms242216366 - 15 Nov 2023

Cited by 2 | Viewed by 2327

Abstract

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective [...] Read more.

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2− breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study’s inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2− eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2− breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2− eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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Review

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13 pages, 880 KiB

Open AccessReview

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions

by Jin Sun Lee, Hannah Hackbart, Xiaojiang Cui and Yuan Yuan

Int. J. Mol. Sci. 2023, 24(14), 11791; https://doi.org/10.3390/ijms241411791 - 22 Jul 2023

Cited by 4 | Viewed by 2451

Abstract

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains [...] Read more.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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