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2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers
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2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 January 2024) | Viewed by 9759

Special Issue Editors

Prof. Dr. Christos Papadimitriou

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Guest Editor
Second Department of Surgery, Aretaieion Hospital, Medical School, National and Kapodistrian University of Athens, 11528 Athens, Greece
Interests: early breast cancer; adjuvant chemotherapy; chemotherapy for metastatic breast cancer; clinical trials; mTOR inhibitors; CDK4/6 inhibitors; endocrine therapy
Special Issues, Collections and Topics in MDPI journals
Dr. Angelos Koutras

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Guest Editor
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, 26504 Patras, Greece
Interests: breast cancer
Dr. Eleni Timotheadou

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Guest Editor
Medical Oncologist, Medical Oncology Clinic Aristotle University of Thessaloniki, Papageorgiou Hospital, 56429 Thessaloniki, Greece
Interests: breast cancer; gynecologic cancer; genetic counseling; translational research
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

This collection is the second edition of the previous Special Issue "Estrogen Receptor-Positive (ER+) Breast Cancers":
https://www.mdpi.com/journal/cancers/special_issues/ER_Cancers

The majority of breast cancers express estrogen and/or progesterone receptors (ER and PR). ER is the primary transcription factor driving oncogenesis in hormone receptor-positive (HR+) breast cancer; it is both the predictor and the target of response to antiestrogen therapy. In tumors without concomitant HER2 amplification, endocrine therapy, aimed at the therapeutic blockade of ER signaling, forms the backbone of treatment for all disease stages; adjuvant endocrine therapy alone
reduces the relative risk of recurrence by nearly 40%. Endocrine therapies include aromatase inhibitors (AIs), gonadotropin-releasing hormone (GnRH) agonists, selective ER modulators (SERMs), and selective ER downregulators (SERDs). Despite its wide therapeutic efficacy, endocrine therapy eventually fails in the majority of patients with metastatic and in a proportion of patients with ER+, HER2- early breast cancer who develop endocrine resistance, resulting in disease recurrence. A number of resistance mechanisms can lead to estrogen-independent growth of HR+ breast cancer as a result of genetic and epigenetic alterations, which could be exploited as novel therapeutic targets. This Special Issue focuses on the biology of ER and the implications of ESR1 mutations in HR+ breast cancer, the role of neoadjuvant therapy, the use of multigene assays to select treatment for early disease, the optimal management of premenopausal patients with ER+ breast cancer, the role of extended adjuvant endocrine therapy, the molecular mechanisms mediating endocrine resistance that emphasize the prominent role of the PI3K/Akt/mTOR and CDK4/6/retinoblastoma protein pathways in cancer cell growth and survival, the molecularly targeted agents to overcome or delay endocrine resistance, and potential predictive biomarkers for accurate patient stratification.

Prof. Dr. Christos Papadimitriou
Dr. Angelos Koutras
Dr. Eleni Timotheadou
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Published Papers (5 papers)

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Research

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24 pages, 5419 KiB  
Article
TMEM97/Sigma 2 Receptor Increases Estrogen Receptor α Activity in Promoting Breast Cancer Cell Growth
by Yuanqin Zhang, Xiangwei Fang, Jiuhui Wang and Daotai Nie
Cancers 2023, 15(23), 5691; https://doi.org/10.3390/cancers15235691 - 2 Dec 2023
Viewed by 1185
Abstract
Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. [...] Read more.
Aberrant estrogen receptor (ER) signaling is a major driver of breast tumor growth and progression. Sigma 2 receptor has long been implicated in breast carcinogenesis based on pharmacological studies, but its molecular identity had been elusive until TMEM97 was identified as the receptor. Herein, we report that the TMEM97/sigma 2 receptor is highly expressed in ER-positive breast tumors and its expression is strongly correlated with ERs and progesterone receptors (PRs) but not with HER2 status. High expression levels of TMEM97 are associated with reduced overall survival of patients. Breast cancer cells with increased expression of TMEM97 had a growth advantage over the control cells under both nutrition-limiting and sufficient conditions, while the knockdown of TMEM97 expression reduced tumor cell proliferations. When compared to their vector control cells, MCF7 and T47D cells with increased TMEM97 expression presented increased resistance to tamoxifen treatment and also grew better under estrogen-depleted conditions. The TMEM97/sigma 2 receptor enhanced the ERα transcriptional activities and increased the expression of genes responsive to estrogen treatment. Increased TMEM97 also stimulated the mTOR/S6K1 signaling pathways in the MCF7 and T47D cells. The increased level of active, phosphorylated ERα, and the enhanced resistance to tamoxifen treatment with increased TMEM97, could be blocked by an mTOR inhibitor. The knockdown of TMEM97 expression reduced the ERα and mTOR/S6K1 signaling activities, rendering the cells with an increased sensitivity to tamoxifen. The observations suggest that the TMEM97/sigma 2 receptor is a novel regulator of ERα activities in breast tumor cell growth. Full article
(This article belongs to the Special Issue 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers)
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11 pages, 2121 KiB  
Article
Indirect Treatment Comparison of First-Line CDK4/6-Inhibitors in Post-Menopausal Patients with HR+/HER2− Metastatic Breast Cancer
by Joseph J. Zhao, Khi Yung Fong, Yiong Huak Chan, Jeremy Tey, Shaheenah Dawood, Soo Chin Lee, Richard S. Finn, Raghav Sundar and Joline S. J. Lim
Cancers 2023, 15(18), 4558; https://doi.org/10.3390/cancers15184558 - 14 Sep 2023
Cited by 2 | Viewed by 1758
Abstract
Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2−) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed [...] Read more.
Background: CDK4/6-inhibitors have demonstrated similar efficacy and are considered an effective first-line endocrine treatment of patients with hormone-receptor positive (HR+)/human-epidermal-growth-factor-receptor-2 negative (HER2−) metastatic breast cancer (MBC) in the endpoint of progression-free survival (PFS). Amongst these, palbociclib was first to achieve regulatory approval, followed subsequently by ribociclib and abemaciclib. However, recent updates of overall survival (OS) showed inconsistencies in the OS benefit for palbociclib compared with the other two CDK4/6-inhibitors. With the lack of head-to-head comparison studies, our study sought to compare indirect survival outcomes between CDK4/6-inhibitors in this setting using a novel reconstructive algorithm. Methods: Phase III randomized trials comparing first-line aromatase inhibitor with/without a CDK4/6-inhibitor in post-menopausal patients with HR+/HER2− MBC were identified through systemic review and literature search of online archives of published manuscripts and conference proceedings. A graphical reconstructive algorithm was utilized to retrieve time-to-event data from reported Kaplan-Meier OS and PFS plots to allow for comparison of survival outcomes. Survival analyses were conducted with Cox proportional-hazards model with a shared-frailty term. Results: Three randomized phase III trials—PALOMA-2, MONALEESA-2 and MONARCH-3—comprising 1827 patients were included. Indirect pairwise comparisons of all CDK4/6-inhibitors showed no significant PFS differences (all p > 0.05). Likewise, indirect treatment comparison between ribociclib vs. palbociclib (one-stage: HR = 0.903, 95%-CI: 0.746–1.094, p = 0.297), abemaciclib vs. palbociclib (one-stage: HR = 0.843, 95%-CI: 0.690–1.030, p = 0.094) and abemaciclib vs. ribociclib (one-stage: HR = 0.933, 95%-CI: 0.753–1.157, p = 0.528) failed to demonstrate a significant OS difference. Conclusions: Findings from this indirect treatment comparison suggest no significant PFS or OS differences between CDK4/6-inhibitors in post-menopausal patients with HR+/HER2− MBC. Full article
(This article belongs to the Special Issue 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers)
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Review

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21 pages, 797 KiB  
Review
Current Status and Future Perspectives of Antibody–Drug Conjugates in Hormone Receptor-Positive Breast Cancer
by Maria Grammoustianou, Foteinos-Ioannis Dimitrakopoulos and Angelos Koutras
Cancers 2024, 16(10), 1801; https://doi.org/10.3390/cancers16101801 - 8 May 2024
Viewed by 601
Abstract
Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of [...] Read more.
Breast cancer is the most common cancer type in women. The vast majority of breast cancer patients have hormone receptor-positive (HR+) tumors. In advanced HR+ breast cancer, the combination of endocrine therapy with cyclin-dependent kinase 4/6 (CDK4/6) inhibitors is considered the standard of care in the front-line setting. Nevertheless, resistance to hormonal therapy and CDK4/6 inhibitors eventually occurs, leading to progression of the disease. Antibody–drug conjugates (ADCs) comprise a promising therapeutic choice with significant efficacy in patients with HR+ breast cancer, which is resistant to endocrine treatment. ADCs typically consist of a cytotoxic payload attached by a linker to a monoclonal antibody that targets a specific tumor-associated antigen, offering the advantage of a more selective delivery of chemotherapy to cancer cells. In this review, we focus on the ADC mechanisms of action, their toxicity profile and therapeutic uses as well as on related biomarkers and future perspectives in advanced HR+ breast cancer. Full article
(This article belongs to the Special Issue 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers)
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21 pages, 3622 KiB  
Review
ESR1 Gene Mutations and Liquid Biopsy in ER-Positive Breast Cancers: A Small Step Forward, a Giant Leap for Personalization of Endocrine Therapy?
by Margaux Betz, Vincent Massard, Pauline Gilson, Andréa Witz, Julie Dardare, Alexandre Harlé and Jean-Louis Merlin
Cancers 2023, 15(21), 5169; https://doi.org/10.3390/cancers15215169 - 27 Oct 2023
Viewed by 1957
Abstract
The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment [...] Read more.
The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2− ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care. Full article
(This article belongs to the Special Issue 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers)
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28 pages, 2770 KiB  
Review
Estrogen Receptor Signaling in Breast Cancer
by Paulina Miziak, Marzena Baran, Ewa Błaszczak, Alicja Przybyszewska-Podstawka, Joanna Kałafut, Jolanta Smok-Kalwat, Magdalena Dmoszyńska-Graniczka, Michał Kiełbus and Andrzej Stepulak
Cancers 2023, 15(19), 4689; https://doi.org/10.3390/cancers15194689 - 23 Sep 2023
Cited by 7 | Viewed by 3870
Abstract
Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors [...] Read more.
Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens’ synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies’ development. Full article
(This article belongs to the Special Issue 2nd Edition: Estrogen Receptor-Positive (ER+) Breast Cancers)
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