Update on adjuvant hormonal treatment of early breast cancer

Romera, Juan Lao; Hernández, Teresa de Jesús Puertolas; Fernández, Ignacio Peláez; Gimeno, Teresa Sampedro; Martínez, Roberto Fernández; Pérez, Isaura Fernández; Cruz, Vega; Mañas, José Juan Illarramendi; Juan, Salvador Garcerá; Gil, Eva

doi:10.1007/s12325-011-0017-1

Cited by 9 publications

(7 citation statements)

References 29 publications

(13 reference statements)

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“…Estrogen plays a crucial role in the progression of hormone-dependent breast cancer via the activation of estrogen receptors (ERs) encoded by ESR1 . By suppressing estrogen production, aromatase inhibitor (AI) treatments are essential parts of the therapeutic repertoire for ER + postmenopausal breast cancers [ 1 , 2 , 3 , 4 , 5 , 6 ]. Unexpectedly, several clinical trials have reported a therapeutic benefit of estrogen for AI-resistant advanced breast cancer [ 7 , 8 , 9 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Mori

Saeki

Chang

et al. 2021

Cancers

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A 100% ER positivity is not required for an endocrine therapy response. Furthermore, while estrogen typically promotes the progression of hormone-dependent breast cancer via the activation of estrogen receptor (ER)-α, estrogen-induced tumor suppression in ER+ breast cancer has been clinically observed. With the success in establishing estrogen-stimulated (SC31) and estrogen-suppressed (GS3) patient-derived xenograft (PDX) models, single-cell RNA sequencing analysis was performed to determine the impact of estrogen on ESR1+ and ESR1– tumor cells. We found that 17β-estradiol (E2)-induced suppression of GS3 transpired through wild-type and unamplified ERα. E2 upregulated the expression of estrogen-dependent genes in both SC31 and GS3; however, E2 induced cell cycle advance in SC31, while it resulted in cell cycle arrest in GS3. Importantly, these gene expression changes occurred in both ESR1+ and ESR1– cells within the same breast tumors, demonstrating for the first time a differential effect of estrogen on ESR1– cells. E2 also upregulated a tumor-suppressor gene, IL-24, in GS3. The apoptosis gene set was upregulated and the G2M checkpoint gene set was downregulated in most IL-24+ cells after E2 treatment. In summary, estrogen affected pathologically defined ER+ tumors differently, influencing both ESR1+ and ESR1– cells. Our results also suggest IL-24 to be a potential marker of estrogen-suppressed tumors.

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Section: Introductionmentioning

confidence: 99%

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Mori

Saeki

Chang

et al. 2021

Cancers

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“…Surgery-specific and general pain were measured using an extended version of the Breast Cancer Pain Questionnaire (BCPQ) and Brief Pain Inventory (BPI), respectively. A Pain Severity Index (PSI) score was calculated using: PSI = Σ(Pain score at each site [0-10]) × (frequency [1][2][3][4][5]). 27 The BCPQ assessed the impact of surgical pain on physical activities relevant to the body area (physical impact of pain).…”

Section: Methodsmentioning

confidence: 99%

Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery

Zhu

Loggia

Edwards³

et al. 2022

The Clinical Journal of Pain

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Objectives: Aromatase inhibitors (AIs), which potently inhibit estrogen biosynthesis, are a standard treatment for hormone sensitive early-stage breast cancer. AIs have been associated with substantial joint pain and muscle stiffness (aromatase inhibitor-associated musculoskeletal syndrome). However, the link between AIs and number of clinical pain locations and pain sensitivity are less well understood. The aim of this study was to compare longitudinal changes in clinical pain and quantitative pain sensitivity between women who did or did not receive AI therapy. Methods: Women with early-stage breast cancer were prospectively enrolled and assessed for clinical pain in surgical and nonsurgical body areas using the Brief Pain Inventory and Breast Cancer Pain Questionnaire, and for pain sensitivity using quantitative sensory testing preoperatively and at 1 year postoperatively. Pain outcomes between participants who did and did not begin adjuvant AI therapy were compared using Wilcoxon Signed-Ranks and generalized estimating equation linear regression analyses. Results: Clinical pain and pain sensitivity were comparable between AI (n=49) and no-AI (n=106) groups preoperatively. After adjusting for body mass index, AI therapy was associated with a greater increase in the number of painful nonsurgical body sites (significant time by treatment interaction, P=0.024). Pain location was most frequent in knees (28%), lower back (26%), and ankles/feet (17%). Quantitative sensory testing revealed a significant decrease in pain sensitivity (increased pressure pain threshold) in the no-AI group over time, but not in the AI group. Conclusions: AI therapy was associated with increased diffuse joint-related pain and greater post-treatment pain sensitivity, potentially implicating central sensitization as a contributing pain mechanism of aromatase inhibitor-associated musculoskeletal syndrome worthy of future investigation.

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“…This phenotype was preserved across serially transplanted GS3 tumors (up to 14 passages so far). GS3 tumor pieces that were simultaneously transplanted with E2, showed no growth for half a year; meanwhile GS3 tumor pieces implanted alongside a placebo pellet (no E2) grew beyond 1000 mm 3 (Fig. 1b).…”

Section: E2 Treatment Inhibited the Proliferation Of Gs3 In Vivo And mentioning

confidence: 99%

“…S1c). After tumor volume reached approximately 200mm 3 , mice were randomized and implanted with an E2 (1 mg) or placebo pellet on their backside. These treatments lasted 7 days for experiments on single cell analysis and lasted 5 days, 10 days, 28 days, and 53 days for bulk RNA sequencing (RNAseq) experiments.…”

Section: In Vivo Animal Studymentioning

confidence: 99%

“…Estrogen, such as 17β-estradiol (E2), plays a crucial role in the progression of hormone-dependent breast cancer through activation of estrogen receptor (ER). By suppressing estrogen production, aromatase inhibitors (AIs) are the rst choice for ER + /HER2 − postmenopausal breast cancer [1][2][3], and they improve the outcomes of these patients [4][5][6]. Clinically, AI resistance is frequent [5].…”

Section: Introductionmentioning

confidence: 99%

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Estrogen-Induced Cell Cycle Arrest and Apoptosis as an Unexpected Outcome of Aromatase Inhibitor-Resistance in ER+ Breast Cancer

Mori

Saeki

Chang

et al. 2021

Preprint

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Background: Estrogen is known to promotes hormone-dependent breast cancer through activation of estrogen receptor (ER)-α encoded by ESR1. However, several clinical trials reported the unexpected therapeutic benefit of E2 for aromatase inhibitor (AI)-resistant cases of ER+ breast cancer. Considering potential impact of such clinical observation, we decided to determine the mechanisms of estrogen-induced tumor regression. Methods: A unique estrogen-inhibitory patient-derived xenograft (PDX) tumor, GS3, was established from an AI resistant ER+/HER2– brain metastatic breast cancer. In vivo estrogen suppression was confirmed through experiments by implanting 17β-estradiol (E2) pellets in mice carrying GS3, and then the single-cell analysis was performed using GS3 tumors. In vitro E2 suppression analysis was carried out using organoids from GS3.Results: The E2-induced suppression of GS3 involves ERα, which was wild-type and not amplified. Single cell RNA sequencing analysis of this PDX has revealed that E2 treatment (for 1 week) induces cell cycle arrest in both ESR1+ cells and ESR1– cells, demonstrating the unexpected influence of estrogen on ESR1– cells in ER+ breast cancer. E2 upregulated the expression of estrogen-regulated genes, including a tumor suppressor gene, IL24, and lower levels of IL24 were linked to estrogen independence, after three rounds of intermittent E2 treatment. IL24+ cells included more G1 phase cells of cell cycle compared to IL24– cells. Hallmark apoptosis gene sets were upregulated and the hallmark G2M checkpoint gene set was downregulated in IL24+ cells after E2 treatment. The number of apoptotic cells was significantly increased after long term (for 4 weeks) E2 treatment. Western blotting analysis demonstrated that long term E2 treatment induced expression of apoptosis-associated protein cleaved-PARP and reduction of the pro-survival protein Bcl-xl level.Conclusions: There is the need of markers for patients who can benefit from E2 treatment after AI resistance, and measurements of ER and PR expression are not enough. Analysis of GS3 PDX has revealed that estrogen induces cell cycle arrest and apoptosis. Our study has revealed the cross-talk between ESR1+ and ESR1– cells as well as potential roles of IL24 in estrogen-suppressive tumors.

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Update on adjuvant hormonal treatment of early breast cancer

Cited by 9 publications

References 29 publications

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery

Estrogen-Induced Cell Cycle Arrest and Apoptosis as an Unexpected Outcome of Aromatase Inhibitor-Resistance in ER+ Breast Cancer

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Update on adjuvant hormonal treatment of early breast cancer

Cited by 9 publications

References 29 publications

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Influence of Estrogen Treatment on ESR1+ and ESR1− Cells in ER+ Breast Cancer: Insights from Single-Cell Analysis of Patient-Derived Xenograft Models

Increased Clinical Pain Locations and Pain Sensitivity in Women After Breast Cancer Surgery

Estrogen-Induced Cell Cycle Arrest and Apoptosis as an Unexpected Outcome of Aromatase Inhibitor-Resistance in ER+&nbsp;Breast Cancer

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Estrogen-Induced Cell Cycle Arrest and Apoptosis as an Unexpected Outcome of Aromatase Inhibitor-Resistance in ER+ Breast Cancer