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Hormone Receptor in Breast Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (20 October 2024) | Viewed by 22203

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Special Issue Editor

Dr. Rocío García-Becerra

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Guest Editor

Instituto de Investigaciones Biomedicas de la UNAM, Mexico City, Mexico
Interests: estrogen receptor; progesterone receptor; androgen receptor; endocrine therapy; corepressors; coactivators; vitamin D receptor

Special Issue Information

Dear Colleagues,

Several factors have been implicated in the pathogenesis of breast cancer. In this vein, about 5–10 % of all breast cancers can be attributed to inherited gene mutations, and the remainder are generally associated with environmental, reproductive, and lifestyle factors. Exposure to chemicals like endocrine disruptor compounds is related to a predisposition to developing breast cancer since these compounds interact with hormone receptors. Additionally, reproductive factors related to the time of exposure to estrogens in the woman's life have been frequently implicated in the risk and causation of breast cancer. These include developing menarche at an early age of menarche or menopause at a late age of menopause, late age of first pregnancy, nulliparity or low parity, and prolonged use of hormone replacement therapy. Obesity increases the risk of developing breast cancer in pre-and postmenopausal women. In contrast, some consumption of compound naturals, such as phytoestrogens (like resveratrol), may be protective. Since hormone factors are crucial for the oncogenesis of breast cancer, endocrine treatment is of significant therapeutic value in patients with estrogen receptor-positive tumors, including selective estrogen–receptor modulators (SERMs), such as tamoxifen and raloxifene, aromatase inhibitors, and Fulvestrant. Although estrogen and progesterone receptors are crucial in the classification and carcinogenesis of mammary tumors, androgen receptor signaling has also influenced the triple-negative breast cancer subtype.

Therefore, authors are invited to submit original research and review articles that address the progress and current state of the art of breast cancer hormone receptors.

The topics of this Special issue Include, but are not limited to:

Hormone receptor signaling pathways;
Breast cancer and pregnancy;
Combinations of antineoplastic with anti-hormone treatments;
Hormonal prevention of breast cancer;
Endocrine therapies.

Dr. Rocío García-Becerra
Guest Editor

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Keywords

estradiol
progesterone
calcitriol
androgen
resveratrol
phytoestrogens
therapeutic targets
fulvestrant
treatment response
SERM
estrogen receptor isoforms
selective ligands
hormonal carcinogenesis
breast cancer prevention
hormone signaling
endocrine disruptor compounds
ER-negative breast cancer
ER-positive breast cancer
aromatase inhibitors

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Published Papers (10 papers)

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Research

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14 pages, 6846 KiB

Open AccessArticle

Pathological Changes Following Neoadjuvant Endocrine Therapy (NAET): A Multicentre Study of 391 Breast Cancers

by Islam M. Miligy, Nahla Badr, Andrea Stevens, David Spooner, Rachna Awasthi, Yasmeen Mir, Anuj Khurana, Vijay Sharma, Usha Chandaran, Emad A. Rakha, Yasmine Maurice, Daniel Kearns, Rami Oweis, Amal Asar, Alastair Ironside and Abeer M. Shaaban

Int. J. Mol. Sci. 2024, 25(13), 7381; https://doi.org/10.3390/ijms25137381 - 5 Jul 2024

Viewed by 1076

Abstract

Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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16 pages, 2877 KiB

Open AccessArticle

Loss of Hormone Receptor Expression after Exposure to Fluid Shear Stress in Breast Cancer Cell Lines

by Jonathan Cuccia, Braulio Andrés Ortega Quesada, Ethan P. Littlefield, Alejandra M. Ham, Matthew E. Burow, Adam T. Melvin and Elizabeth C. Martin

Int. J. Mol. Sci. 2024, 25(13), 7119; https://doi.org/10.3390/ijms25137119 - 28 Jun 2024

Viewed by 1070

Abstract

Following metastatic spread, many hormone receptor positive (HR⁺) patients develop a more aggressive phenotype with an observed loss of the HRs estrogen receptor (ER) and progesterone receptor (PR). During metastasis, breast cancer cells are exposed to high magnitudes of fluid shear stress (FSS). Unfortunately, the role for FSS on the regulation of HR expression and function during metastasis is not fully understood. This study was designed to elucidate the impact of FSS on HR⁺ breast cancer. Utilizing a microfluidic platform capable of exposing breast cancer cells to FSS that mimics in situ conditions, we demonstrate the impact of FSS exposure on representative HR⁺ breast cancer cell lines through protein and gene expression analysis. Proteomics results demonstrated that 540 total proteins and 1473 phospho-proteins significantly changed due to FSS exposure and pathways of interest included early and late estrogen response. The impact of FSS on response to 17β-estradiol (E2) was next evaluated and gene expression analysis revealed repression of ER and E2-mediated genes (PR and SDF1) following exposure to FSS. Western blot demonstrated enhanced phosphorylation of mTOR following exposure to FSS. Taken together, these studies provide initial insight into the effects of FSS on HR signaling in metastatic breast cancer. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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21 pages, 3314 KiB

Open AccessArticle

EB1089 Increases the Antiproliferative Response of Lapatinib in Combination with Antiestrogens in HER2-Positive Breast Cancer Cells

by Angèle Sorel Achounna, David Ordaz-Rosado, Janice García-Quiroz, Gabriela Morales-Guadarrama, Edgar Milo-Rocha, Fernando Larrea, Lorenza Díaz and Rocío García-Becerra

Int. J. Mol. Sci. 2024, 25(6), 3165; https://doi.org/10.3390/ijms25063165 - 9 Mar 2024

Cited by 1 | Viewed by 1215

Abstract

HER2-positive breast cancer is associated with aggressive behavior and reduced survival rates. Calcitriol restores the antiproliferative activity of antiestrogens in estrogen receptor (ER)-negative breast cancer cells by re-expressing ERα. Furthermore, calcitriol and its analog, EB1089, enhance responses to standard anti-cancer drugs. Therefore, we aimed to investigate EB1089 effects when added to the combined treatment of lapatinib and antiestrogens on the proliferation of HER2-positive breast cancer cells. BT-474 (ER-positive/HER2-positive) and SK-BR-3 (ER-negative/HER2-positive) cells were pre-treated with EB1089 to modulate ER expression. Then, cells were treated with EB1089 in the presence of lapatinib with or without the antiestrogens, and proliferation, phosphorylation array assays, and Western blot analysis were performed. The results showed that EB1089 restored the antiproliferative response to antiestrogens in SK-BR-3 cells and improved the inhibitory effects of the combination of lapatinib with antiestrogens in the two cell lines. Moreover, EB1089, alone or combined, modulated ERα protein expression and reduced Akt phosphorylation in HER2-positive cells. EB1089 significantly enhanced the cell growth inhibitory effect of lapatinib combined with antiestrogens in HER2-positive breast cancer cells by modulating ERα expression and Akt phosphorylation suppression. These results highlight the potential of this therapeutic approach as a promising strategy for managing HER2-positive breast cancer. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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Review

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13 pages, 754 KiB

Open AccessReview

The Evolving Role of Genomic Testing in Early Breast Cancer: Implications for Diagnosis, Prognosis, and Therapy

by Konstantinos Venetis, Carlo Pescia, Giulia Cursano, Chiara Frascarelli, Eltjona Mane, Elisa De Camilli, Elisabetta Munzone, Silvia Dellapasqua, Carmen Criscitiello, Giuseppe Curigliano, Elena Guerini Rocco and Nicola Fusco

Int. J. Mol. Sci. 2024, 25(11), 5717; https://doi.org/10.3390/ijms25115717 - 24 May 2024

Viewed by 2701

Abstract

Multigene prognostic genomic assays have become indispensable in managing early breast cancer (EBC), offering crucial information for risk stratification and guiding adjuvant treatment strategies in conjunction with traditional clinicopathological parameters. The American Society of Clinical Oncology (ASCO) guidelines endorse these assays, though some clinical contexts still lack definitive recommendations. The dynamic landscape of EBC management demands further refinement and optimization of genomic assays to streamline their incorporation into clinical practice. The breast cancer community is poised at the brink of transformative advances in enhancing the clinical utility of genomic assays, aiming to significantly improve the precision and effectiveness of both diagnosis and treatment for women with EBC. This article methodically examines the testing methodologies, clinical validity and utility, costs, diagnostic frameworks, and methodologies of the established genomic tests, including the Oncotype Dx Breast Recurrence Score^®, MammaPrint, Prosigna^®, EndoPredict^®, and Breast Cancer Index (BCI). Among these tests, Prosigna and EndoPredict^® have at present been validated only on a prognostic level, while Oncotype Dx, MammaPrint, and BCI hold both a prognostic and predictive role. Oncologists and pathologists engaged in the management of EBC will find in this review a thorough comparison of available genomic assays, as well as strategies to optimize the utilization of the information derived from them. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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28 pages, 2326 KiB

Open AccessReview

A Representative Clinical Course of Progression, with Molecular Insights, of Hormone Receptor-Positive, HER2-Negative Bone Metastatic Breast Cancer

by Elizabeth Magno and Karen M. Bussard

Int. J. Mol. Sci. 2024, 25(6), 3407; https://doi.org/10.3390/ijms25063407 - 17 Mar 2024

Cited by 2 | Viewed by 2120

Abstract

Despite treatment advances, breast cancer remains a leading cause of death of women in the United States, mostly due to metastatic disease. Bone is a preferential site for breast cancer metastasis, and most metastatic breast cancer patients experience bone involvement at the time of death. The majority of patients with bone metastatic breast cancer are first diagnosed with and treated for early-stage disease, and from development of early-stage breast cancer to the recurrence of cancer in the bones, up to 30 years may elapse. Throughout this timeframe, a typical patient undergoes many treatments that have effects on the bone microenvironment. Therefore, this review explores the clinical course of a representative patient with hormone receptor-positive bone metastatic breast cancer, examining key treatment options at each stage and their effects on preventing and treating bone metastases. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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24 pages, 1010 KiB

Open AccessReview

Treatments Targeting the Androgen Receptor and Its Splice Variants in Breast Cancer

by Amy H. Tien and Marianne D. Sadar

Int. J. Mol. Sci. 2024, 25(3), 1817; https://doi.org/10.3390/ijms25031817 - 2 Feb 2024

Cited by 4 | Viewed by 2486

Abstract

Breast cancer is a major cause of death worldwide. The complexity of endocrine regulation in breast cancer may allow the cancer cells to escape from a particular treatment and result in resistant and aggressive disease. These breast cancers usually have fewer treatment options. Targeted therapies for cancer patients may offer fewer adverse side effects because of specificity compared to conventional chemotherapy. Signaling pathways of nuclear receptors, such as the estrogen receptor (ER), have been intensively studied and used as therapeutic targets. Recently, the role of the androgen receptor (AR) in breast cancer is gaining greater attention as a therapeutic target and as a prognostic biomarker. The expression of constitutively active truncated AR splice variants in breast cancer is a possible mechanism contributing to treatment resistance. Therefore, targeting both the full-length AR and AR variants, either through the activation or suppression of AR function, depending on the status of the ER, progesterone receptor, or human epidermal growth factor receptor 2, may provide additional treatment options. Studies targeting AR in combination with other treatment strategies are ongoing in clinical trials. The determination of the status of nuclear receptors to classify and identify patient subgroups will facilitate optimized and targeted combination therapies. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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26 pages, 2613 KiB

Open AccessReview

Hormone, Targeted, and Combinational Therapies for Breast Cancers: From Humans to Dogs

by Chiao-Hsu Ke, Chao-Nan Lin and Chen-Si Lin

Int. J. Mol. Sci. 2024, 25(2), 732; https://doi.org/10.3390/ijms25020732 - 5 Jan 2024

Viewed by 2696

Abstract

Breast cancer (BC) is the most frequent cancer in women. In female dogs, canine mammary gland tumor (CMT) is also the leading neoplasm. Comparative oncology indicates similar tumor behaviors between human BCs (HBCs) and CMTs. Therefore, this review summarizes the current research in hormone and targeted therapies and describes the future prospects for HBCs and CMTs. For hormone receptor-expressing BCs, the first medical intervention is hormone therapy. Monoclonal antibodies against Her2 are proposed for the treatment of Her2+ BCs. However, the major obstacle in hormone therapy or monoclonal antibodies is drug resistance. Therefore, increasing alternatives have been developed to overcome these difficulties. We systemically reviewed publications that reported inhibitors targeting certain molecules in BC cells. The various treatment choices for humans decrease mortality in females with BC. However, the development of hormone or targeted therapies in veterinary medicine is still limited. Even though some clinical trials have been proposed, severe side effects and insufficient case numbers might restrict further explorations. This difficulty highlights the urgent need to develop updated hormone/targeted therapy or novel immunotherapies. Therefore, exploring new therapies to provide more precise use in dogs with CMTs will be the focus of future research. Furthermore, due to the similarities shared by humans and dogs, well-planned prospective clinical trials on the use of combinational or novel immunotherapies in dogs with CMTs to obtain solid results for both humans and dogs can be reasonably anticipated in the future. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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13 pages, 883 KiB

Open AccessReview

Androgen Receptor in Hormone Receptor-Positive Breast Cancer

by Ashfia Fatima Khan, Samaneh Karami, Anthony S. Peidl, Kacie D. Waiters, Mariam Funmi Babajide and Tasneem Bawa-Khalfe

Int. J. Mol. Sci. 2024, 25(1), 476; https://doi.org/10.3390/ijms25010476 - 29 Dec 2023

Cited by 1 | Viewed by 2175

Abstract

Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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15 pages, 3199 KiB

Open AccessReview

GPER: An Estrogen Receptor Key in Metastasis and Tumoral Microenvironments

by Ana Carolina Tirado-Garibay, Elba Andrea Falcón-Ruiz, Alejandra Ochoa-Zarzosa and Joel E. López-Meza

Int. J. Mol. Sci. 2023, 24(19), 14993; https://doi.org/10.3390/ijms241914993 - 8 Oct 2023

Cited by 2 | Viewed by 2642

Abstract

Estrogens and their role in cancer are well-studied, and some cancer types are classified in terms of their response to them. In recent years, a G protein-coupled estrogen receptor (GPER) has been described with relevance in cancer. GPER is a pleiotropic receptor with tissue-specific activity; in normal tissues, its activation is related to correct development and homeostasis, while in cancer cells, it can be pro- or anti-tumorigenic. Also, GPER replaces estrogen responsiveness in estrogen receptor alpha (ERα)-lacking cancer cell lines. One of the most outstanding activities of GPER is its role in epithelial–mesenchymal transition (EMT), which is relevant for metastasis development. In addition, the presence of this receptor in tumor microenvironment cells contributes to the phenotypic plasticity required for the dissemination and maintenance of tumors. These characteristics suggest that GPER could be a promising therapeutic target for regulating cancer development. This review focuses on the role of GPER in EMT in tumorigenic and associated cells, highlighting its role in relation to the main hallmarks of cancer and possible therapeutic options. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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20 pages, 1611 KiB

Open AccessReview

Modulation of JAK-STAT Signaling by LNK: A Forgotten Oncogenic Pathway in Hormone Receptor-Positive Breast Cancer

by José A. López-Mejía, Jessica C. Mantilla-Ollarves and Leticia Rocha-Zavaleta

Int. J. Mol. Sci. 2023, 24(19), 14777; https://doi.org/10.3390/ijms241914777 - 30 Sep 2023

Cited by 10 | Viewed by 2599

Abstract

Breast cancer remains the most frequently diagnosed cancer in women worldwide. Tumors that express hormone receptors account for 75% of all cases. Understanding alternative signaling cascades is important for finding new therapeutic targets for hormone receptor-positive breast cancer patients. JAK-STAT signaling is commonly activated in hormone receptor-positive breast tumors, inducing inflammation, proliferation, migration, and treatment resistance in cancer cells. In hormone receptor-positive breast cancer, the JAK-STAT cascade is stimulated by hormones and cytokines, such as prolactin and IL-6. In normal cells, JAK-STAT is inhibited by the action of the adaptor protein, LNK. However, the role of LNK in breast tumors is not fully understood. This review compiles published reports on the expression and activation of the JAK-STAT pathway by IL-6 and prolactin and potential inhibition of the cascade by LNK in hormone receptor-positive breast cancer. Additionally, it includes analyses of available datasets to determine the level of expression of LNK and various members of the JAK-STAT family for the purpose of establishing associations between expression and clinical outcomes. Together, experimental evidence and in silico studies provide a better understanding of the potential implications of the JAK-STAT-LNK loop in hormone receptor-positive breast cancer progression. Full article

(This article belongs to the Special Issue Hormone Receptor in Breast Cancer)

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