ER positive

Unlike the canonical activation of PAR1 by thrombin, which enhances cell proliferation via mechanistic target of rapamycin (mTOR) signaling, HAP-induced noncanonical activation downregulates mTOR activation and triggers autophagy in both estrogen receptor positive/ progesterone receptor positive/ HER2 negative (ER+/PR+/HER2-) and triple negative (ER-/PR-/HER2-) breast cancer cells...Importantly, the lack of PAR1 expression in normal, healthy breast epithelial cells facilitates the peptide to selectively target breast cancer cells with relatively high PAR1 expression, highlighting its potential as a therapeutic agent against low-grade malignant breast tumor. These findings provide valuable insights into autophagy activation by a synthetic peptide that targets breast cancer cells with high PAR1 expression and for the first time shows peptide mediated targeted therapy of low-grade malignant breast tumor.

PROTACs, especially ER degraders, suggest a potential strategy for addressing endocrine resistance in advanced ER + breast cancer, as reflected in encouraging preliminary clinical data. This integrated analysis highlights the rapid translation of this technology while underscoring the critical need to expand target scope, address inherent resistance mechanisms, and broaden applications to other breast cancer subtypes. Our article synthesizes current knowledge and trial landscape, thereby providing a consolidated foundation to inform future research and clinical development of PROTACs in breast cancer.

P4, N=80, Not yet recruiting, Hospital Universitari de Bellvitge | Trial completion date: Sep 2028 --> Jan 2035 | Initiation date: Sep 2026 --> Jan 2027 | Trial primary completion date: May 2027 --> Apr 2031

Mechanistically, our data indicate that ELF1 transcriptionally regulates EGFR and that ERK1/2 interacts with ELF1, suggesting the existence of a positive ELF1/EGFR/ERK feedback loop that sustains resistance. This study elucidates a possible mechanism of resistance to AR inhibition driven by an ELF1/EGFR/ERK feedback loop in AR-Vs positive cells and provides a rationale for combining EGFR inhibitors with AR-targeted therapy as a potential treatment strategy for patients with advanced, enzalutamide-resistant prostate cancer.

P=N/A, N=68, Active, not recruiting, Mayo Clinic | Trial completion date: Mar 2026 --> Mar 2028 | Trial primary completion date: Mar 2026 --> Mar 2028

P3, N=1556, Suspended, Alliance for Clinical Trials in Oncology | N=1156 --> 1556

Routine assessment of ESR1 mutations using liquid biopsy should be integrated into clinical practice to enable dynamic, molecularly guided treatment optimization. The expanding arsenal of ER-targeted therapies supports personalized sequencing strategies that move beyond rigid temporal cutoffs and improve outcomes in ET resistant disease.

We investigated whether DHED could prevent side effects associated with the aromatase inhibitor letrozole in a primate model of aging...Here, we show that a brain-selective estrogen therapy administered orally via the prodrug DHED substantially increases estrogen levels in the marmoset brain without affecting the periphery and normalizes impairments in working memory, hippocampal neuronal excitability and sleep induced by aromatase inhibition. These findings in a translational primate model represent a significant advance for women's health by positioning DHED as a non-invasive, safe and efficient novel hormone therapy to improve quality of life of women with ER+ breast cancers.

Functional perturbation experiments in ER+ breast cancer cells showed that TGF-β stimulation enhanced invasive behavior, whereas knockdown of MMP1 or COL7A1 attenuated epithelial-mesenchymal transition (EMT) marker expression and invasion. Together, our study delineates RBP-associated regulatory programs linking cellular state transitions to invasive signaling in ER+ breast cancer.

P1, N=48, Recruiting, Novartis Pharmaceuticals | Active, not recruiting --> Recruiting

PDZK1 functions as a regulator of HER2 stability and may serve as a potential biomarker and therapeutic target in HER2-positive breast cancer. Pharmacological upregulation of PDZK1 may represent a promising combinatorial therapeutic strategy for overcoming therapeutic resistance in breast cancer.

In the tamoxifen resistance context, PAK1 inhibition induced activation of the pro-apoptotic protein BAD and triggered apoptosis while proliferation-related kinases were suppressed in the estrogen-deprived model. Our findings position PAK1 as a mediator of resistance to endocrine therapies suggesting that targeting PAK1 may present a novel strategy to overcome endocrine therapy resistance in ER+ breast cancer.