scholarly journals Estetrol and Mammary Gland: Friends or Foes?

2021 ◽  
Author(s):  
Anne Gallez ◽  
Isabelle Dias Da Silva ◽  
Vincent Wuidar ◽  
Jean-Michel Foidart ◽  
Christel Péqueux
Keyword(s):  
Breast Cancer ◽  
Mammary Gland ◽  
Hormone Replacement ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Estrogenic Action ◽  
Estrogenic Properties ◽  
Preclinical And Clinical Studies ◽  
Crucial Part ◽  
Menopause Hormone Therapy

AbstractEstrogens have pleiotropic effects on many reproductive and non-reproductive tissues and organs including the mammary gland, uterus, ovaries, vagina, and endothelium. Estrogen receptor α functions as the principal mediator of estrogenic action in most of these tissues. Estetrol (E4) is a native fetal estrogen with selective tissue actions that is currently approved for use as the estrogen component in a combined oral contraceptive and is being developed as a menopause hormone therapy (MHT, also known as hormone replacement therapy). However, exogenous hormonal treatments, in particular MHTs, have been shown to promote the growth of preexisting breast cancers and are associated with a variable risk of breast cancer depending on the treatment modality. Therefore, evaluating the safety of E4-based formulations on the breast forms a crucial part of the clinical development process. This review highlights preclinical and clinical studies that have assessed the effects of E4 and E4-progestogen combinations on the mammary gland and breast cancer, focusing in particular on the estrogenic and anti-estrogenic properties of E4. We discuss the potential advantages of E4 over current available estrogen-formulations as a contraceptive and for the treatment of symptoms due to menopause. We also consider the potential of E4 for the treatment of endocrine-resistant breast cancer.

scholarly journals Estrogens and Progestogens in Triple Negative Breast Cancer: Do They Harm?

Cancers ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2506
Author(s):  
Mark van Barele ◽  
Bernadette A. M. Heemskerk-Gerritsen ◽  
Yvonne V. Louwers ◽  
Mijntje B. Vastbinder ◽  
John W. M. Martens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Triple Negative ◽  
Hormone Replacement ◽  
Breast Cancers ◽  
Younger Women ◽  
Alternative Pathways ◽  
Increased Risk ◽  
History Of ◽  
Hormone Sensitive

Triple-negative breast cancers (TNBC) occur more frequently in younger women and do not express estrogen receptor (ER) nor progesterone receptor (PR), and are therefore often considered hormone-insensitive. Treatment of premenopausal TNBC patients almost always includes chemotherapy, which may lead to premature ovarian insufficiency (POI) and can severely impact quality of life. Hormone replacement therapy (HRT) is contraindicated for patients with a history of hormone-sensitive breast cancer, but the data on safety for TNBC patients is inconclusive, with a few randomized trials showing increased risk-ratios with wide confidence intervals for recurrence after HRT. Here, we review the literature on alternative pathways from the classical ER/PR. We find that for both estrogens and progestogens, potential alternatives exist for exerting their effects on TNBC, ranging from receptor conversion, to alternative receptors capable of binding estrogens, as well as paracrine pathways, such as RANK/RANKL, which can cause progestogens to indirectly stimulate growth and metastasis of TNBC. Finally, HRT may also influence other hormones, such as androgens, and their effects on TNBCs expressing androgen receptors (AR). Concluding, the assumption that TNBC is completely hormone-insensitive is incorrect. However, the direction of the effects of the alternative pathways is not always clear, and will need to be investigated further.

ARE BREAST CANCERS IN PATIENTS ON HORMONE REPLACEMENT THERAPY DIFFERENT FROM THE CLASSICAL BREAST CANCER?

2003 ◽  
Vol 13 (Suppl 1) ◽  
pp. 30.1-30
Author(s):  
M. Aerts ◽  
P. Neven ◽  
R. Drijkoningen ◽  
L. Morales ◽  
R. Paridaens ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Hormone Replacement ◽  
Breast Cancers

scholarly journals Type 1 Nuclear Receptor Activity in Breast Cancer: Translating Preclinical Insights to the Clinic

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4972
Author(s):  
Sanjeev Kumar ◽  
Allegra Freelander ◽  
Elgene Lim
Keyword(s):  
Breast Cancer ◽  
Nuclear Receptors ◽  
Nuclear Receptor ◽  
Patient Outcomes ◽  
Estrogen Receptor Α ◽  
Receptor Activity ◽  
Breast Cancers ◽  
Cancer Subtypes ◽  
Major Breast

The nuclear receptor (NR) family of transcription factors is intimately associated with the development, progression and treatment of breast cancer. They are used diagnostically and prognostically, and crosstalk between nuclear receptor pathways and growth factor signalling has been demonstrated in all major subtypes of breast cancer. The majority of breast cancers are driven by estrogen receptor α (ER), and anti-estrogenic therapies remain the backbone of treatment, leading to clinically impactful improvements in patient outcomes. This serves as a blueprint for the development of therapies targeting other nuclear receptors. More recently, pivotal findings into modulating the progesterone (PR) and androgen receptors (AR), with accompanying mechanistic insights into NR crosstalk and interactions with other proliferative pathways, have led to clinical trials in all of the major breast cancer subtypes. A growing body of evidence now supports targeting other Type 1 nuclear receptors such as the glucocorticoid receptor (GR), as well as Type 2 NRs such as the vitamin D receptor (VDR). Here, we reviewed the existing preclinical insights into nuclear receptor activity in breast cancer, with a focus on Type 1 NRs. We also discussed the potential to translate these findings into improving patient outcomes.

scholarly journals Review of: Tamoxifen and TRAIL synergistically induce apoptosis in breast cancer cells

2008 ◽  
Vol 11 (2) ◽  
Author(s):  
Alison J. Butt
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Single Agent ◽  
Xenograft Model ◽  
Estrogen Receptor Α ◽  
Tumor Xenograft ◽  
Breast Cancers ◽  
Induced Apoptosis

Citation of original article:C. Lagadec, E. Adriaenssens, R. A. Toillon, V. Chopin, R. Romon, F. Van Coppenolle, H. Hondermarck, X. Le Bourhis. Oncogene advance online publication, 3 September 2007; doi:10.1038/sj.onc.1210749.Abstract of the original article:Tamoxifen (TAM), is widely used as a single agent in adjuvant treatment of breast cancer. Here, we investigated the effects of TAM in combination with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in estrogen receptor-α (ER-α)-positive and -negative breast cancer cells. We showed that cotreatment with TAM and TRAIL synergistically induced apoptosis regardless of ER-α status. By contrast, cotreatment did not affect the viability of normal breast epithelial cells. Cotreatment with TAM and TRAIL in breast cancer cells decreased the levels of antiapoptotic proteins including FLIPs and Bcl-2, and enhanced the levels of proapoptotic proteins such as FADD, caspase 8, tBid, Bax and caspase 9. Furthermore, cotreatment-induced apoptosis was efficiently reduced by FADD- or Bid-siRNA, indicating the implication of both extrinsic and intrinsic pathways in synergistic apoptosis induction. Importantly, cotreatment totally arrested tumor growth in an ER-α-negative MDA-MB-231 tumor xenograft model. The abrogation of tumor growth correlated with enhanced apoptosis in tumor tissues. Our findings raise the possibility to use TAM in combination with TRAIL for breast cancers, regardless of ER-α status.

scholarly journals Ligand-Selective Interdomain Conformations of Estrogen Receptor-α

2007 ◽  
Vol 21 (1) ◽  
pp. 49-61 ◽  
Author(s):  
Adrian Padron ◽  
Li Li ◽  
Eric M. Kofoed ◽  
Fred Schaufele
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Energy Transfer ◽  
Hormone Replacement ◽  
Estrogen Receptor Α ◽  
Full Length ◽  
Estrogen Receptor Modulators ◽  
Interaction Kinetics ◽  
Receptor Modulators

Abstract Selective estrogen receptor modulators (SERMs) inhibit estrogen activation of the estrogen receptor (ER) in some tissues but activate ER in other tissues. These tissue-selective actions suggest that SERMs may be identified with tissue specificities that would improve the safety of breast cancer and hormone replacement therapies. The identification of an improved SERM would be aided by understanding the effects of each SERM on the structure and interactions of ER. To date, the inability to obtain structures of the full-length ER has limited our structural characterization of SERM action to their antiestrogenic effects on the isolated ER ligand binding domain. We studied the effects of estradiol and the clinically useful SERMs 4-hydroxytamoxifen and fulvestrant on the conformation of the full-length ERα dimer complex by comparing, in living human breast cancer cells, the amounts of energy transfer between fluorophores attached to different domains of ERα. Estradiol, 4-hydroxytamoxifen, and fulvestrant all promoted the rapid formation of ERα dimers with equivalent interaction kinetics. The amino- and carboxyl-terminal ERα domains both contain activation functions differentially affected by these ligands, but the positions of only the carboxyl termini differed upon binding with estradiol, 4-hydroxytamoxifen, or fulvestrant. The association of a specific ERα dimer conformation with the binding of ligands of different clinical effect will assist the identification of a SERM with optimal tissue-selective estrogenic and antiestrogenic activities. These studies also provide a roadmap for dissecting important structural and kinetic details for any protein complex from the quantitative analysis of energy transfer.

scholarly journals Increased expression of the estrogen receptor alpha, ESR1, in the tumors of breast cancer patients treated with trastuzumab.

2020 ◽  
Author(s):  
Shahan Mamoor
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Estrogen Receptor Α ◽  
Needle Aspiration ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Primary Tumors ◽  
Transcriptional Induction ◽  
Selection Of

Hormones function as growth factors, and estrogen provides growth signals to support and induce the proliferation of breast cancers (1-3). This is the basis of the use of endocrine therapies (4, 5) including tamoxifen and letrozole as first-line treatment for patients with breast cancer. We found through mining published microarray and multiplexed gene expression profiling datasets that the estrogen receptor α (ESR1) was among the genes most differentially expressed in the primary tumors and fine needle aspiration-isolated tumor cells of patients with breast cancer treated with trastuzumab. However, estrogen receptor α was expressed at higher rather than lower levels in the tumors of trastuzumab-treated patients. These data, obtained through blind, systems-level analysis of published microarray data (6-8), suggest that trastuzumab administration in patients with breast cancer is associated with transcriptional induction of the estrogen receptor or selection of tumor clones with high expression of ESR1.

scholarly journals Androgen Receptor as an Emerging Feasible Biomarker for Breast Cancer

Biomolecules ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 72
Author(s):  
Chan-Ping You ◽  
Man-Hong Leung ◽  
Wai-Chung Tsang ◽  
Ui-Soon Khoo ◽  
Ho Tsoi
Keyword(s):  
Breast Cancer ◽  
Androgen Receptor ◽  
Growth Factor Receptor ◽  
Estrogen Receptor Α ◽  
Nuclear Hormone Receptor ◽  
Tumor Promoter ◽  
Breast Cancers ◽  
Scoring Method ◽  
Poor Prognostic Factor ◽  
Prognosis And Prediction

Biomarkers can be used for diagnosis, prognosis, and prediction in targeted therapy. The estrogen receptor α (ERα) and human epidermal growth factor receptor 2 (HER2) are standard biomarkers used in breast cancer for guiding disease treatment. The androgen receptor (AR), a nuclear hormone receptor, contributes to the development and progression of prostate tumors and other cancers. With increasing evidence to support that AR plays an essential role in breast cancer, AR has been considered a useful biomarker in breast cancer, depending on the context of breast cancer sub-types. The existing survival analyses suggest that AR acts as a tumor suppressor in ER + ve breast cancers, serving as a favorable prognostic marker. However, AR functions as a tumor promoter in ER-ve breast cancers, including HER2 + ve and triple-negative (TNBC) breast cancers, serving as a poor prognostic factor. AR has also been shown to be predictive of the potential of response to adjuvant hormonal therapy in ER + ve breast cancers and to neoadjuvant chemotherapy in TNBC. However, conflicting results do exist due to intrinsic molecular differences between tumors and the scoring method for AR positivity. Applying AR expression status to guide treatment in different breast cancer sub-types has been suggested. In the future, AR will be a feasible biomarker for breast cancer. Clinical trials using AR antagonists in breast cancer are active. Targeting AR alone or other therapeutic agents provides alternatives to existing therapy for breast cancer. Therefore, AR expression will be necessary if AR-targeted treatment is to be used.

scholarly journals The Other Side of the Coin: May Androgens Have a Role in Breast Cancer Risk?

2021 ◽  
Vol 23 (1) ◽  
pp. 424
Author(s):  
Chiara Chiodo ◽  
Catia Morelli ◽  
Fabiola Cavaliere ◽  
Diego Sisci ◽  
Marilena Lanzino
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Risk ◽  
Cancer Risk ◽  
Breast Tissue ◽  
Estrogen Receptor Α ◽  
Epidemiological Studies ◽  
Breast Cancers ◽  
Cancer Risk Factors ◽  
Increased Risk ◽  
The Impact

Breast cancer prevention is a major challenge worldwide. During the last few years, efforts have been made to identify molecular breast tissue factors that could be linked to an increased risk of developing the disease in healthy women. In this concern, steroid hormones and their receptors are key players since they are deeply involved in the growth, development and lifetime changes of the mammary gland and play a crucial role in breast cancer development and progression. In particular, androgens, by binding their own receptor, seem to exert a dichotomous effect, as they reduce cell proliferation in estrogen receptor α positive (ERα+) breast cancers while promoting tumour growth in the ERα negative ones. Despite this intricate role in cancer, very little is known about the impact of androgen receptor (AR)-mediated signalling on normal breast tissue and its correlation to breast cancer risk factors. Through an accurate collection of experimental and epidemiological studies, this review aims to elucidate whether androgens might influence the susceptibility for breast cancer. Moreover, the possibility to exploit the AR as a useful marker to predict the disease will be also evaluated.

scholarly journals GREB1 isoforms regulate proliferation independent of ERα co-regulator activities in breast cancer

2018 ◽  
Vol 25 (7) ◽  
pp. 735-746 ◽  
Author(s):  
Corinne N Haines ◽  
Kara M Braunreiter ◽  
Xiaokui Molly Mo ◽  
Craig J Burd
Keyword(s):  
Breast Cancer ◽  
Growth Regulation ◽  
Target Genes ◽  
Estrogen Receptor Α ◽  
Breast Cancers ◽  
Gene Target ◽  
Elevated Expression ◽  
Malignant Breast ◽  
Exogenous Expression ◽  
Specific Regulation

Activation of the transcription factor estrogen receptor α (ERα) and the subsequent regulation of estrogen-responsive genes play a crucial role in the development and progression of the majority of breast cancers. One gene target of ERα, growth regulation by estrogen in breast cancer 1 (GREB1), is associated with proliferation and regulation of ERα activity in estrogen-responsive breast cancer cells. The GREB1 gene encodes three distinct isoforms: GREB1a, GREB1b and GREB1c, whose molecular functions are largely unknown. Here, we investigate the role of these isoforms in regulation of ERα activity and proliferation. Interaction between GREB1 and ERα was mapped to the amino terminus shared by all GREB1 variants. Analysis of isoform-specific regulation of ERα activity suggests none of the GREB1 isoforms possess potent co-regulator activity. Exogenous expression of GREB1a resulted in elevated expression of some ER-target genes, independent of ERα activity. Despite this slight specificity of GREB1a for gene regulation, exogenous expression of either GREB1a or GREB1b resulted in decreased proliferation in both ER-positive and ER-negative breast carcinoma cell lines, demonstrating an ER-independent function of GREB1. Interestingly, we show an increase in the expression of GREB1b and GREB1c mRNA in malignant breast tissue compared to normal patient samples, suggesting a selective preference for these isoforms during malignant transformation. Together, these data suggest GREB1a has an isoform-specific function as a transcriptional regulator while all isoforms share an ER-independent activity that regulates proliferation.

Hormone replacement therapy (HRT) in women with previously treated primary breast cancer: Update XIII

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 11044-11044
Author(s):  
A. Z. Bluming
Keyword(s):  
Breast Cancer ◽  
Median Duration ◽  
Primary Breast Cancer ◽  
Hormone Replacement ◽  
Disease Free Survival ◽  
Breast Cancer Diagnosis ◽  
Breast Cancers ◽  
Local Recurrences ◽  
Initial Surgery ◽  
Previously Treated

11044 Background: To assess the incidence of contralateral or recurrent breast cancer among women prospectively treated with HRT after initial breast cancer diagnosis. Methods: A community-based, prospective, single-arm, pilot study of HRT among 246 women with previously treated primary breast cancer. Results: Median duration of HRT is 89+ months (range 12+ -173+). Median interval from initial surgery to initiation of HRT is 52 months (range 2–361 months). Follow-up to date is 100%. Actuarial disease-free survival (DFS), disease-specific survival (DSS), & median duration of HRT by stage are listed in the table : *T0N0: 2 LCIS recurred locally after lumpectomy alone. 2 DCIS recurred locally after lumpectomy/RT 5 contralateral tumors (3 DCIS, 2 T1N0) 1 distant recurrence - liver. (alive 4 years later). **T1N0: 9 local recurrences after lumpectomy/RT 7 contralateral tumors. 8 distant recurrences - 3 lung, 2 liver, 3 bone - 4 died ***T2N0: 2 local recurrences after lumpectomy/RT 2 distant recurrences - lung - 1 died ****T1N1: 3 local recurrence after lumpectomy/RT 2 contralateral tumors 2 distant recurrences - 1 bone, 1 supraclav node - 2 died ***** T2–3N1: 1 contralateral tumor 3 distant recurrences - 1 cerv node-2 bone mets - 2 died One hundred and sixteen patients have stopped HRT (47%), 57 because of anxiety about taking HRT (23%), 50 because of breast cancer development (20%), 3 because of the development of non-breast cancers, 2 died of nonmalignant disease, 3 because of HRT-associated symptoms, and 1 because of pulmonary emboli without clinical phlebitis. CHRT, as opposed to ERT, was administered to 50% of all patients and 58% of the 50 who subsequently developed breast cancer on study. Actuarial DFS to 25 years for T1N0 patients was 67% versus 37% (DSS=86%) for comparable T1N0 patients who did not receive HRT. Conclusions: No evidence to date of increased development, recurrence or of breast cancer-related death associated with post diagnosis HRT. [Table: see text] No significant financial relationships to disclose.

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