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Cancers
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Breast Cancer and Hormone-Related Therapy
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Breast Cancer and Hormone-Related Therapy

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

Deadline for manuscript submissions: 20 November 2024 | Viewed by 15845

Special Issue Editor

Dr. John R. Hawse

E-Mail Website
Guest Editor
Mayo Clinic, Rochester, MN, USA
Interests: molecular biology; breast cancer; estrogen receptor; hormone-based therapy

Special Issue Information

Dear Colleagues,

Breast cancer remains the most common malignancy in women and over 70% of all breast tumors are initially characterized as being “hormonally sensitive” based on expression of estrogen receptor alpha (ERα). ERα positive tumors are known to be driven by estrogens and, as such, numerous therapies have been developed to either directly target ERα (such as tamoxifen and fulvestrant) or to suppress the production of estrogen throughout the body through the use of ovarian function suppression and/or aromatase inhibitors. More recently, a newer class of drugs known as CDK4/6 inhibitors have demonstrated profound activity in the metastatic setting and are now commonly used in combination with aromatase inhibitors as a first line therapy for patients with recurrent ERα positive tumors.

In addition to ERα, a number of other hormone activated transcription factors, including ERβ, progesterone receptor, androgen receptor, and glucocorticoid receptor, have been shown to be expressed in breast cancer, and substantial efforts have been made to determine the contribution of these factors in breast cancer development, progression, and treatment. As a result of these efforts, and the world-wide uptake of many different forms of hormonal therapy, breast cancer has become a more manageable disease. However, with the significant extension of lifespan comes the increased probability of treatment failure, disease recurrence, and the diminution in the efficacy of additional hormone-based treatment strategies.

This Special Issue relates to emerging hormonal therapies, both for newly diagnosed and resistant forms of breast cancer, the molecular mechanisms by which such therapies elicit their anti-cancer effects and the cellular processes that are ultimately responsible for treatment failure.

Dr. John R. Hawse
Guest Editor

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.

Keywords

  • breast cancer
  • estrogen receptor
  • hormone activated transcription factors
  • hormonal therapy
  • molecular mechanisms

Published Papers (8 papers)

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Research

Jump to: Review

15 pages, 2687 KiB  
Article
Long-Term Oral Tamoxifen Administration Decreases Brain-Derived Neurotrophic Factor in the Hippocampus of Female Long-Evans Rats
by Laura E. Been, Amanda R. Halliday, Sarah M. Blossom, Elena M. Bien, Anya G. Bernhard, Grayson E. Roth, Karina I. Domenech Rosario, Karlie B. Pollock, Petra E. Abramenko, Leily M. Behbehani, Gabriel J. Pascal and Mary Ellen Kelly
Cancers 2024, 16(7), 1373; https://doi.org/10.3390/cancers16071373 - 31 Mar 2024
Viewed by 627
Abstract
Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic [...] Read more.
Tamoxifen, a selective estrogen receptor modulator (SERM), is commonly used as an adjuvant drug therapy for estrogen-receptor-positive breast cancers. Though effective at reducing the rate of cancer recurrence, patients often report unwanted cognitive and affective side effects. Despite this, the impacts of chronic tamoxifen exposure on the brain are poorly understood, and rodent models of tamoxifen exposure do not replicate the chronic oral administration seen in patients. We, therefore, used long-term ad lib consumption of medicated food pellets to model chronic tamoxifen exposure in a clinically relevant way. Adult female Long-Evans Hooded rats consumed tamoxifen-medicated food pellets for approximately 12 weeks, while control animals received standard chow. At the conclusion of the experiment, blood and brain samples were collected for analyses. Blood tamoxifen levels were measured using a novel ultra-performance liquid chromatography–tandem mass spectrometry assay, which found that this administration paradigm produced serum levels of tamoxifen similar to those in human patients. In the brain, brain-derived neurotrophic factor (BDNF) was visualized in the hippocampus using immunohistochemistry. Chronic oral tamoxifen treatment resulted in a decrease in BDNF expression across several regions of the hippocampus. These findings provide a novel method of modeling and measuring chronic oral tamoxifen exposure and suggest a putative mechanism by which tamoxifen may cause cognitive and behavioral changes reported by patients. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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20 pages, 7001 KiB  
Article
Modulation of Estrogen Receptor Alpha (ERα) and Tumor Suppressor Gene BRCA1 in Breast Cancer Cells by Bazedoxifene Acetate (BZA)
by Monica Szmyd, Aisha Zanib, Victoria Behlow, Erin Hallman, Samantha Pfiffner, Raquel Yaldo, Nina Prudhomme, Katelyn Farrar and Sumi Dinda
Cancers 2024, 16(4), 699; https://doi.org/10.3390/cancers16040699 - 07 Feb 2024
Viewed by 998
Abstract
Selective estrogen receptor modulators (SERMs) are steroid analogs with dual functionality, acting as partial estrogen receptor agonists to preserve postmenopausal bone density and as estrogen receptor antagonists in breast tissue. Bazedoxifene acetate (BZA) is an FDA-approved, third-generation SERM used in the treatment of [...] Read more.
Selective estrogen receptor modulators (SERMs) are steroid analogs with dual functionality, acting as partial estrogen receptor agonists to preserve postmenopausal bone density and as estrogen receptor antagonists in breast tissue. Bazedoxifene acetate (BZA) is an FDA-approved, third-generation SERM used in the treatment of osteoporosis in women. It demonstrates potential as a therapeutic option for breast cancer patients undergoing endocrine therapy. Our study aimed to assess BZA’s effects on Estrogen Receptor Alpha (ERα) and tumor suppressor gene BRCA1 in T-47D and MCF-7 breast cancer cells, using Western blots, cellular viability, apoptosis assays, and RT-qPCR. Cells were cultured in 5% charcoal-stripped fetal bovine serum for six days to deplete endogenous steroids. Following a 24 h exposure to 2 µM BZA (optimal concentration determined from 1 nM–2 µM studies), Western blot analyses revealed reduced ERα and BRCA1 protein levels in both cell lines. ERα decreased by 48–63% and BRCA1 by 61–64%, indicating sensitivity to antiestrogens. Cytolocalization of ERα and BRCA1 remained unchanged after BZA and 17-β-estradiol (E2) treatment. ESR1 mRNA expression correlated with Western blot findings. Image cytometric analysis using the stain, propidium iodide, detected decreased cellular proliferation in T-47D and MCF-7 cells following a 6-day treatment ranging from 1 nM to 2 µM BZA. BZA treatment alone led to a tenfold reduction in cellular proliferation compared to estrogen-treated cells, suggesting antiproliferative effects. Understanding BZA’s modulation of BRCA1 and ERα, along with their mechanistic interactions, is vital for comprehending its impact on breast cancer tumor suppressors and hormone receptors. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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19 pages, 6307 KiB  
Article
Glucocorticoid Receptor Activation in Lobular Breast Cancer Is Associated with Reduced Cell Proliferation and Promotion of Metastases
by Baylee A. Porter, Candace Frerich, Muriel Lainé, Abigail B. Clark, Ishrat Durdana, Jeon Lee, Manisha Taya, Sunati Sahoo, Geoffrey L. Greene, Lynda Bennett and Suzanne D. Conzen
Cancers 2023, 15(19), 4679; https://doi.org/10.3390/cancers15194679 - 22 Sep 2023
Viewed by 1312
Abstract
Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern [...] Read more.
Estrogen receptor-positive (ER+) invasive lobular breast cancer (ILC) comprises about ~15% of breast cancer. ILC’s unique genotypic (loss of wild type E-cadherin expression) and phenotypic (small individual round cancer cells that grow in discontinuous nests) are thought to contribute to a distinctive pattern of metastases to serosal membranes. Unlike invasive ductal carcinoma (IDC), ILC metastases often intercalate into the mesothelial layer of the peritoneum and other serosal surfaces. While ER activity is a known driver of ILC proliferation, very little is known about how additional nuclear receptors contribute to ILC’s distinctive biology. In ER+ IDC, we showed previously that glucocorticoid receptor (GR) activity inhibits pro-proliferative gene expression and cell proliferation. Here we examined ER+ ILC models and found that GR activation similarly reduces S-phase entry gene expression and ILC proliferation. While slowing tumor growth rate, our data also suggest that GR activation results in an enhanced metastatic phenotype through increasing integrin-encoding gene expression, extracellular matrix protein adhesion, and mesothelial cell clearance. Moreover, in an intraductal mouse mammary gland model of ILC, we found that GR expression is associated with increased bone metastases despite slowed primary mammary tumor growth. Taken together, our findings suggest GR-mediated gene expression may contribute to the unusual characteristics of ILC biology. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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21 pages, 7339 KiB  
Article
Stratification of Tamoxifen Synergistic Combinations for the Treatment of ER+ Breast Cancer
by Emily K. Zboril, Jacqueline M. Grible, David C. Boyd, Nicole S. Hairr, Tess J. Leftwich, Madelyn F. Esquivel, Alex K. Duong, Scott A. Turner, Andrea Ferreira-Gonzalez, Amy L. Olex, Carol A. Sartorius, Mikhail G. Dozmorov and J. Chuck Harrell
Cancers 2023, 15(12), 3179; https://doi.org/10.3390/cancers15123179 - 14 Jun 2023
Viewed by 1976
Abstract
Breast cancer alone accounts for the majority of cancer deaths among women, with the most commonly diagnosed subtype being estrogen receptor positive (ER+). Survival has greatly improved for patients with ER+ breast cancer, due in part to the development of antiestrogen compounds, such [...] Read more.
Breast cancer alone accounts for the majority of cancer deaths among women, with the most commonly diagnosed subtype being estrogen receptor positive (ER+). Survival has greatly improved for patients with ER+ breast cancer, due in part to the development of antiestrogen compounds, such as tamoxifen. While treatment of the primary disease is often successful, as many as 30% of patients will experience recurrence and metastasis, mainly due to developed endocrine therapy resistance. In this study, we discovered two tamoxifen combination therapies, with simeprevir and VX-680, that reduce the tumor burden in animal models of ER+ breast cancer more than either compound or tamoxifen alone. Additionally, these tamoxifen combinations reduced the expression of HER2, a hallmark of tamoxifen treatment, which can facilitate acquisition of a treatment-resistant phenotype. These combinations could provide clinical benefit by potentiating tamoxifen treatment in ER+ breast cancer. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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25 pages, 6877 KiB  
Article
Investigating the Role of Heparanase in Breast Cancer Development Utilising the MMTV-PyMT Murine Model of Mammary Carcinoma
by Krishnath M. Jayatilleke, Hendrika M. Duivenvoorden, Gemma F. Ryan, Belinda S. Parker and Mark D. Hulett
Cancers 2023, 15(11), 3062; https://doi.org/10.3390/cancers15113062 - 05 Jun 2023
Viewed by 1564
Abstract
Breast cancer is the second most common human malignancy and is a major global health burden. Heparanase (HPSE) has been widely implicated in enhancing the development and progression of solid tumours, including breast cancer. In this study, the well-established spontaneous mammary tumour-developing MMTV-PyMT [...] Read more.
Breast cancer is the second most common human malignancy and is a major global health burden. Heparanase (HPSE) has been widely implicated in enhancing the development and progression of solid tumours, including breast cancer. In this study, the well-established spontaneous mammary tumour-developing MMTV-PyMT murine model was utilised to examine the role of HPSE in breast cancer establishment, progression, and metastasis. The use of HPSE-deficient MMTV-PyMT (MMTV-PyMTxHPSE−/−) mice addressed the lack of genetic ablation models to investigate the role of HPSE in mammary tumours. It was demonstrated that even though HPSE regulated mammary tumour angiogenesis, mammary tumour progression and metastasis were HPSE-independent. Furthermore, there was no evidence of compensatory action by matrix metalloproteinases (MMPs) in response to the lack of HPSE expression in the mammary tumours. These findings suggest that HPSE may not play a significant role in the mammary tumour development of MMTV-PyMT animals. Collectively, these observations may have implications in the clinical setting of breast cancer and therapy using HPSE inhibitors. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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44 pages, 9684 KiB  
Article
Discovery of Highly Functionalized 5-hydroxy-2H-pyrrol-2-ones That Exhibit Antiestrogenic Effects in Breast and Endometrial Cancer Cells and Potentiate the Antitumoral Effect of Tamoxifen
by Miguel Guerra-Rodríguez, Priscila López-Rojas, Ángel Amesty, Haidée Aranda-Tavío, Yeray Brito-Casillas, Ana Estévez-Braun, Leandro Fernández-Pérez, Borja Guerra and Carlota Recio
Cancers 2022, 14(21), 5174; https://doi.org/10.3390/cancers14215174 - 22 Oct 2022
Cited by 2 | Viewed by 1809
Abstract
Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized [...] Read more.
Tamoxifen improves the overall survival rate in hormone receptor-positive breast cancer patients. However, despite the fact that it exerts antagonistic effects on the ERα, it can act as a partial agonist, resulting in tumor growth in estrogen-sensitive tissues. In this study, highly functionalized 5-hydroxy-2H-pyrrol-2-ones were synthesized and evaluated by using ERα- and phenotype-based screening assays. Compounds 32 and 35 inhibited 17β-estradiol (E2)-stimulated ERα-mediated transcription of the luciferase reporter gene in breast cancer cells without inhibition of the transcriptional activity mediated by androgen or glucocorticoid receptors. Compound 32 regulated E2-stimulated ERα-mediated transcription by partial antagonism, whereas compound 35 caused rapid and non-competitive inhibition. Monitoring of 2D and 3D cell growth confirmed potent antitumoral effects of both compounds on ER-positive breast cancer cells. Furthermore, compounds 32 and 35 caused apoptosis and blocked the cell cycle of ER-positive breast cancer cells in the sub-G1 and G0/G1 phases. Interestingly, compound 35 suppressed the functional activity of ERα in the uterus, as demonstrated by the inhibition of E2-stimulated transcription of estrogen and progesterone receptors and alkaline phosphatase enzymatic activity. Compound 35 showed a relatively low binding affinity with ERα. However, its antiestrogenic effect was associated with an increased polyubiquitination and a reduced protein expression of ERα. Clinically relevant, a possible combinatory therapy with compound 35 may enhance the antitumoral efficacy of 4-hydroxy-tamoxifen in ER-positive breast cancer cells. In silico ADME predictions indicated that these compounds exhibit good drug-likeness, which, together with their potential antitumoral effects and their lack of estrogenic activity, offers a pharmacological opportunity to deepen the study of ER-positive breast cancer treatment. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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Review

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20 pages, 8148 KiB  
Review
Therapies for the Treatment of Advanced/Metastatic Estrogen Receptor-Positive Breast Cancer: Current Situation and Future Directions
by Rohan Kalyan Rej, Joyeeta Roy and Srinivasa Rao Allu
Cancers 2024, 16(3), 552; https://doi.org/10.3390/cancers16030552 - 27 Jan 2024
Cited by 1 | Viewed by 1636
Abstract
The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment [...] Read more.
The hormone receptor-positive (HR+) type is the most frequently identified subtype of breast cancer. HR+ breast cancer has a more positive prognosis when compared to other subtypes, such as human epidermal growth factor protein 2-positive disorder and triple-negative disease. The advancement in treatment outcomes for advanced HR+ breast cancer has been considerably elevated due to the discovery of cyclin-dependent kinase 4/6 inhibitors and their combination effects with endocrine therapy. However, despite the considerable effectiveness of tamoxifen, a selective estrogen receptor modulator (SERMs), and aromatase inhibitors (AI), the issue of treatment resistance still presents a significant challenge for HR+ breast cancer. As a result, there is a focus on exploring new therapeutic strategies such as targeted protein degradation and covalent inhibition for targeting ERα. This article discusses the latest progress in treatments like oral selective ER degraders (SERDs), complete estrogen receptor antagonists (CERANs), selective estrogen receptor covalent antagonists (SERCAs), proteolysis targeting chimera (PROTAC) degraders, and combinations of CDK4/6 inhibitors with endocrine therapy. The focus is specifically on those compounds that have transitioned into phases of clinical development. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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17 pages, 1786 KiB  
Review
The Potential of Hormonal Therapies for Treatment of Triple-Negative Breast Cancer
by Melanie Kirkby, Alyanna M. Popatia, Jessie R. Lavoie and Lisheng Wang
Cancers 2023, 15(19), 4702; https://doi.org/10.3390/cancers15194702 - 24 Sep 2023
Cited by 1 | Viewed by 5067
Abstract
Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth [...] Read more.
Triple-negative breast cancer (TNBC) is considered one of the most aggressive forms of breast cancer with poor survival rates compared to other breast cancer subtypes. TNBC is characterized by the absence of the estrogen receptor alpha, progesterone receptor, and the human epidermal growth factor receptor 2, limiting those viable treatment options available to patients with other breast cancer subtypes. Furthermore, due to the particularly high heterogeneity of TNBC, conventional treatments such as chemotherapy are not universally effective, leading to drug resistance and intolerable side effects. Thus, there is a pressing need to discover new therapies beneficial to TNBC patients. This review highlights current findings regarding the roles of three steroid hormone receptors, estrogen receptor beta, the androgen receptor, and the glucocorticoid receptor, in the progression of TNBC. In addition, we discussed several ongoing and completed clinical trials targeting these hormone receptors in TNBC patients. Full article
(This article belongs to the Special Issue Breast Cancer and Hormone-Related Therapy)
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Planned Papers

The below list represents only planned manuscripts. Some of these manuscripts have not been received by the Editorial Office yet. Papers submitted to MDPI journals are subject to peer-review.

Title: Triple negative breast cancer and bazedoxifen
Authors: Rosa Sirianni
Affiliation: Università della Calabria, Cosenza, Italy

Title: hormonal treatment options in metastatic breast cancer after progression to a first line with cyclin inhibitors
Authors: Serafin Morales
Affiliation: HOSPITAL UNIVERSITARI ARNAU DE VILANOVA DE LLEIDA

Title: related to an exciting concept of photodynamic therapy targeted at hormone-dependent brat cancer cells
Authors: Marek Murias
Affiliation: Poznan University of Medical Sciences

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