ER overexpression

In our cohort of HR+/HER2- early BC patients, patient menopausal status influenced the correlation between the RS and classical histopathological features. The rate of PgR expression was the only variable consistently correlating with the RS, regardless of menopausal status. Hence, the prognostic and predictive role of this, often overlooked, parameter deserves further investigation in larger and multicentric cohorts, along with a prospective validation.

Methods Pre/perimenopausal pts with no prior systemic therapy for aggressive HR+/HER2− ABC were randomized 1:1 to RIB + letrozole/anastrozole + goserelin or physician's choice of combo CT. Contrary results in the CT arm suggest that these signatures warrant further studies on their potential predictive value. These data are hypothesis generating and should be interpreted with caution due to small sample sizes.

Subsequently, he received androgen deprivation therapy (ADT) for 6 months with triptorelin and bicalutamide...The pathological stage was pT1c pN1mi.The Oncotype DX study had a Recurrence Score (RS) of 22 points, leading to a recommendation for adjuvant chemotherapy with Docetaxel-Cyclophosphamide for 4 cycles, followed by tamoxifen...Early detection through screening and appropriate medical follow-up improves the prognosis in patients carrying PV in BRCA2. Therefore, risk control monitoring and adequate genetic counseling are necessary.

In breast cancers, there is no resistance to genotoxic or immune blocker therapies, but rather, the nonresponsive tumor cells exhaust all compensatory possibilities against therapeutic damages. Understanding the behavior and ambition of breast cancer cells may achieve a turn in therapy via applying supportive care instead of genotoxic measures.

The conditional factor induced by ADA@MOF-EPL further enhances the antitumor efficacy while significantly reducing systemic toxicity. Moreover, ADA@MOF-EPL demonstrates similar antitumor abilities in other p53-mutated solid tumors, revealing its potential as a broad-spectrum antitumor drug.

Clinical assessments suggested diagnostic value for GRPR-targeted theranostics in breast cancer patients, particularly those with high estrogen receptor expression. Nevertheless, in the therapeutic clinical context, paying attention to the radiation dose administered to the pancreas and kidneys is crucial.

The use of steroids and/or antibiotics in the patient prior to sampling can also impact the likelihood of success in PDX development. Lastly, establishing a cutoff point for tumor growth rates could guide the decision-making process during PDX development.

Our study shows that PABC is potentially a clinical and molecular different entity with predominance of the basal-like subtype. Moreover, our results suggest the activation of oncogenic pathways related to cell proliferation, DNA damage repair and p53 mutations which may lead to a clinically more aggressive phenotype for PABC patients. Likewise, the enrichment of BRCAness and HRD signatures found in PABC patients in our study may suggest an increased genetic instability due to a breakdown in the DNA damage repair.

The putative worse prognostic impact of HER2 expression in pts with ER-positive/HER2-negative BCs was not confirmed. The better outcome observed in pts with HER2 2+/FISH- BCs may be related to the known FISH-negative (HER2-non-amplified) status of this subgroup. These findings may help identify optimal patient inclusion criteria for clinical trials with novel anti-HER2 therapies in ER-positive/HER2-negative disease.

Curcumin potentiated the apoptotic effect of venetoclax in NT1-M CLL cells...These cellular effects were associated with reduced NOTCH1 activity in leukemic cells and resulted in prolonged survival of curcumin-treated mice. Overall, our results indicate that ER stress induction in NT1-M CLL might represent a new therapeutic opportunity for these high-risk CLL patients and improve the therapeutic effect of drugs currently used in CLL.

Several drugs have been designed to specifically target ER in ER-positive (ER+) breast cancer, including selective estrogen receptor modulators (SERM) such as Tamoxifen...This paper provides a comprehensive review of the structural functions of ER and highlights recent advancements in SERD and SERCA-related small molecule drugs, especially focusing on their structural optimization strategies and future optimization directions. Additionally, the therapeutic potential and challenges of novel SERDs and SERCAs in breast cancer and other ER-related diseases have been discussed.

We found that HR+ breast cancer cell lines treated with the selective estrogen-degrader fulvestrant, displayed increased B7-H4 levels and combination treatment of EVOLVE-106 with fulvestrant increases EC50 of tumor killing by 5–8 fold. Conclusions These data support the potential positioning of EVOLVE-106 as a first-in-category immunotherapeutic approach for patients with Her2 receptor low breast cancers, and both estrogen receptor positive and negative tumors, including TNBC.

Differentially expressed genes suggested the activation of NOTCH signaling in the passaged organoids, wherein a NOTCH inhibitor was able to substantially rescue the decreased ER expression and alter the differentiation status. Our findings suggest that the differentiation status of luminal-type cancer cells is quite flexible, and that by inhibiting the NOTCH signaling we can preserve the differentiation status of luminal-type breast cancer organoids.

Conclusions The HER2E subtype within ER+/HER2- disease is a small but clinically relevant patient subgroup that is not constituted by misclassified cases and is less ER dependent than other luminal subtypes. It does not represent a distinct biological entity, but it is nevertheless associated with potentially targetable molecular features, for instance in form of a high immune response and high FGFR4 expression.

The better outcome observed in pts with HER2 2+/FISH- BCs may be related to the known FISH-negative (HER2-non-amplified) status of this subgroup. These findings may help identify optimal patient inclusion criteria for clinical trials with novel anti-HER2 therapies in ER-positive/HER2-negative disease.

In this work, low ESR1 levels are associated with poor response, high proliferation, high expression of growth factor pathways and non-luminal subtypes. PRs having high ESR1 expression have similar proportions of luminal subtypes to GRs but lower plasma estradiol levels, lower expression of estrogen response genes, higher levels of tumor infiltrating lymphocytes and immune markers, and more TP53 mutations.

Material and MethodsEndocrine-resistant long-term estrogen-deprived (LTED) and engineered ER-overexpressing ER+ breast cancer cells were treated ± 17b-estradiol and the histone deacetylase inhibitors (HDACi) entinostat or panobinostat. 17b-estradiol in combination with an HDACi is more effective that either drug alone in endocrine-resistant models. The novel combination of an HDACi and 17b-estradiol has the potential to be an effective therapy for patients with endocrine-resistant ER+ breast cancer.

The efficacy of combination therapy with the PARP inhibitor olaparib and 17b-estradiol was analyzed in vitro and in vivo.Results and DiscussionsHigh ER levels converted the estrogen 17b-estradiol from a growth promoter to a growth suppressor, increasing R-loop formation, DNA damage, and apoptosis...ConclusionR-loop-induced DNA damage has the potential to be therapeutically leveraged in breast tumors expressing high ER levels through combination therapy with 17b-estradiol and inhibitors of the DNA damage response. Clinical testing of the combination of 17b-estradiol and a PARP inhibitor is warranted.

There is, however, significant difference of the value of Ki67 proliferation marker. The prognosis of lobular morphology is questionable in our cohort.

Our data provides new insights into the biology of BLBC and identifies the combination of caspase-1/IL1β inhibition and immunotherapy as a novel therapeutic strategy to combat this disease.

The proliferation of NEDD4-knockdown cells treated with tamoxifen or estradiol deprivation was suppressed, compared with that of NEDD4-expressing cells. Knockdown of NEDD4 in breast cancer cells induced the accumulation of estrogen receptor α and increased sensitivity to hormone therapy. In summary, this mechanism may lead to a better prognosis in hormone receptor-positive breast cancer patients with a low expression of NEDD4.

Siglec-15 up-regulates in breast cancer and affects the tumor immune microenvironment. High expression of Siglec-15 before NACT presaged poor efficacy. ER, PR, HER2, Ki-67 and molecular typing before NACT can predict the efficacy as well.

In addition, overexpression of ESR1 significantly reversed the inhibitory effect of ISO on the proliferation, migration and invasion of OC cells. We confirmed that ISO inhibits OC cell proliferation, migration and invasion by targeting ESR1 expression, which provides a theoretical basis for further pharmacological research.

Results demonstrate that, like humans, generation of ER adenocarcinoma in mice was facilitated by aging mice past the age of reproductive senescence. Esr1 overexpression was associated with a proliferative estrogen pathway-linked signature that preceded appearance of ER mammary adenocarcinomas.

This resolved with progression through reproductive senescence in CYP19A1 mice, but was more persistent in Esr1 mice, resolving only with tamoxifen and letrozole exposure. In summary, genetically engineered mouse models of Esr1 and CYP19A1 overexpression revealed a diversion of disease processes resulting from the two distinct molecular pathophysiological mammary gland-targeted intrusions into estrogen signaling during reproductive senescence.

ARV7 expression was independently associated with shorter CRPC-FS (HR 1.5, 95% CI 1.1-2.1, p = 0.008) and OS (HR 1.8, 95% CI 1.2-2.6, p = 0.004), high ESR2 was associated with longer OS (HR 0.5, 95% CI 0.2-1, p = 0.048) and low expression of RB1 was independently associated with shorter OS (HR 1.9, 95% CI 1.1-3.2, p = 0.014). (4) AR, ESR, and TSG expression signatures, as well as ARV7, RB1, and ESR2 expression, have a prognostic value in mHSPC patients treated with ADT+DX.

Peak time was related to a high nuclear-associated antigen Ki-67 index, high ER expression, and high progesterone receptor (PR) expression in breast cancer patients (P<0.05). The quantitative parameters of MRI were associated with clinical pathological characteristics and recurrence or metastasis in breast cancer after surgery.

We observed similar survival outcomes between HER2-low and HER2-zero HR + patients. HER2-low patients had a higher proportion of ER high expressed tumors than HER2-zero patients did. RS and its proliferation module might be less clinically meaningful to HER2-low patients.

We further verified that obese females with a high expression of ESR1 can regulate MMAA to protect HCC from progression. This study elucidates that obesity might be a protective factor for female HCC patients, as they originally highly expressed ESR1, which could upregulate MMAA to suppress tumor growth and participate in metabolic reprogramming.

Since NFKB signaling can be pharmacologically enhanced by the SMAC mimetics, we studied the effect of the combination of Birinapant with Fulvestrant on IFNg response, cytokine secretion, T cell mediated cytotoxicity and migration. Our studies indicate that the transcriptional activity of NFKB is augmented by silencing of ER signaling, suggesting that the crosstalk between ER and NFKB has a key role in the diminished response to IFNg mediated by ER. These results suggest that the combination of endocrine treatment and a SMAC mimetic is a potential novel therapeutic approach to leverage immune based therapies in ER+ BC.

Low expression of LINC02613 predicts poor OS in breast cancer patients. LINC02613 is involved in the regulation of the cell cycle, DNA replication and glycolysis via the Wnt signaling pathway, and it is related to antitumor immunity.

Our data suggest that breast tumors with low levels of ER expression (1-9%, 10-50%) comprise a separate entity within ER-positive breast cancer regarding their immune landscape. Here we show that not only tumors with very low ER levels (1-9%) mimic TNBC in terms of immune landscape but also that tumors with low ER levels (10-50%) might be more likely to respond to ICB than tumors with high levels of ER expression.

H3K27me3 is deposited by EZH2, and inhibition of EZH2 in the context of ARID1A loss results in restoration of estrogen-induced PGR expression. Our results suggest a role for ARID1A deficiency in the loss of PGR in late-stage EC and a therapeutic utility for EZH2 inhibitors in this disease.

Compared to the traditional treatment using BTZ monotherapy, ES-NP can significantly impede disease progression at lower BTZ concentrations and improve its resistance. Moreover, ES-NP demonstrates similar antitumor abilities in patient-derived xenograft animal models and five other types of solid tumor cells, revealing its potential as a broad-spectrum antitumor formulation.

Patients with active migraine had higher estrogen receptor expression, while migraine and TTH patients mainly had HER2 + BC. This association was not known earlier and could be helpful to understand deeper the relationship between BC and headache.

ERlow tumors seemed to have higher recurrence rates compared to ERhigh tumors, and they showed no significant benefit from hormonal therapy. Future large scale prospective studies are necessary to validate the treatment options for ERlow breast cancer.

The combination of F and T was active in this cohort at poor prognosis and deserves further investigations possibly in combination with pertuzumab in patients with high ER expression.

Conclusion Identification of AR driven tumors within TNBC has both prognostic and predictive utility. Methods using limited number of AR regulated genes could be easily applied to larger BC cohorts to identify TNBC tumours driven by AR signalling and may respond well to anti-androgen therapies.

CAM patients who receive multi-modal therapy with curative intent may have OS more comparable to LABC patients than M1 patients. Out data support a reevaluation of whether CAM should remain classified as M1, as N3 may better reflect disease prognosis and treatment goals.