Breast Cancer Research最新文献

Background: Basic helix-loop-helix family, member e22 (BHLHE22), a basic helix loop helix transcription factor family member, functions vary in different types of cancer. Currently, its function in triple-negative breast cancer (TNBC) is unclear.

Methods: The GSE45827 and GSE113865 datasets were used to screen potential TNBC marker. Biological websites were used to analyze BHLHE22 expression in TNBC, its relationship with the prognosis of patients with TNBC, and its potential function. A series of in vitro and in vivo experiments was performed to investigate the function of BHLHE22 in TNBC. The regulatory relationship between OTU domain-containing protein 3 (OTUD3) and BHLHE22 was verified by Co-Immunoprecipitation, ubiquitination assay, and site-specific mutation experiments. The mRNA-seq analysis was performed to identify potential genes for the anti-cancer role of BHLHE22. The transcriptional regulation of DNA replication factor 1 (CDT1) by BHLHE22 was confirmed by dual luciferase reporter assay.

Results: We identified the downregulation of BHLHE22 in TNBC tissues based on the GSE45827 and GSE113865 datasets. The expression of BHLHE22 in TBNC patients was lower than that in non-TNBC patients, and patients at stages 3 and 4 tended to express lower BHLHE22 expression than patients at stages 1 and 2. Patients with high expression of BHLHE22 had better survival prognosis than those with BHLHE22 low expression. Functional studies revealed that BHLHE22 overexpression impaired cell growth in vitro and in vivo. However, BHLHE22 silencing enhanced the malignant behaviors of cancer cells. OTUD3, a deubiquitinase known to suppress TNBC progression, was found to increase the stability of BHLHE22 protein through deubiquitination regulation. The C76 site mutation of OTUD3 eliminated the catalytic activity of OTUD3 and failed to regulate the protein stability of BHLHE22. Furthermore, BHLHE22 medicated the antitumor effect of OTUD3 in TNBC. The mRNA-seq analysis identified potential genes for the anti-cancer role of BHLHE22, involving CDT1. BHLHE22 was proved to reduce CDT1 RNA expression by blocking CDT1 transcription. The anti-proliferative effect of BHLHE22 overexpression was reversed by CDT1 overexpression.

Conclusions: Our observations demonstrate that BHLHE22 may be a promising target for TNBC therapy.

Background: Premenopausal women diagnosed with estrogen receptor (ER)-positive breast cancer are prescribed 5-10 years of tamoxifen therapy to prevent or delay a recurrence. The enzymes 17β-hydroxysteroid dehydrogenase 1 and 2 (HSD17B1 and HSD17B2, respectively) regulate the relative concentrations of estrogen metabolites and may modify tamoxifen effectiveness. We evaluated the prognostic and predictive value of HSD17B1 and HSD17B2 expression in breast tumors.

Methods: We identified a cohort of premenopausal breast cancer patients from the Danish Breast Cancer Group database (2002-2011) and stratified on ER status and receipt of tamoxifen (4600 ER+/TAM + and 1359 ER-/TAM-). Biomarkers HSD17B1 and HSD17B2 were assayed by immunohistochemistry. We used Cox proportional hazards regression to compute the hazard ratios (HRs) and 95% simulation intervals (SIs) associating each biomarker with recurrence, with bias adjustment to account for mismeasurement of biomarker expression and baseline selection bias from tumor sample availability.

Results: Among ER+/TAM + breast cancers, 24% had any HSD17B1 expression compared with 13% of ER-/TAM - breast cancers. In the bias-adjusted analyses, women diagnosed with tumors positive for HSD17B1 expression had a slight increased rate of recurrence: HR = 1.13 (95% SI 0.90, 1.43) in the ER+/TAM + stratum and HR = 1.15 (95% SI 0.77, 1.79) in the ER-/TAM - stratum. A 10-unit increase in HSD17B2 expression corresponded with a decrease in the estimated rate of recurrence among ER+/TAM + patients (HR = 0.85, 95% SI 0.69, 1.05), but not among ER-/TAM - patients (HR = 1.07, 95% SI 0.82, 1.42).

Conclusions: HSD17B1 may be a prognostic marker for recurrence and HSD17B2 may be predictive of response to tamoxifen therapy in breast cancer.

Sequencing of the T-cell receptor (TCR) repertoire can reflect immune status and monitor treatment responses. Here, we aimed to characterize the TCRβ repertoire and its correlation with clinical and prognostic significance in breast cancer. A total of 856 peripheral blood samples were collected from female breast cancer patients for TCR sequencing. At baseline, TCR clonality was elevated in patients with stage IV disease compared with earlier-stage breast cancer, and higher clonality within the stage IV cohort was associated with poorer overall survival. Compared with the luminal A subtype, luminal B2 breast cancer exhibited lower baseline TCR Shannon diversity. Following both adjuvant and neoadjuvant chemotherapy, we observed increased TCR convergence and clonality accompanied by reduced Shannon diversity. Remarkably, these repertoire changes were most evident in patients treated with taxane or anthracycline plus taxane regimens in the adjuvant setting, and with anthracycline plus taxane or platinum-based regimens in the neoadjuvant setting. Notably, trastuzumab was associated with increased clonality and reduced diversity in HER2-enriched tumors, but not in Luminal B2. Lower TCR richness in post-treatment blood samples was associated with patients achieving pathologic complete response in the neoadjuvant setting. This study provides comprehensive circulating TCR repertoire metric profiles across the heterogeneous population of breast cancer patients.

Background: Evidence regarding the aetiology of specific breast cancer subtypes may provide insights into the mechanisms underlying their development, and improve prevention of rarer but more aggressive subtypes. We investigated risk factor associations with surrogate molecular subtypes of breast cancer in a large cohort of UK women.

Methods: In 1.2 million postmenopausal women aged 50-64 recruited into the Million Women Study in 1996-2001, we estimated risks of breast cancer subtypes (defined by oestrogen receptor [ER], progesterone receptor [PR], and human epidermal growth factor receptor 2 [HER2] status) in relation to established risk factors for breast cancer.

Results: Among 1,228,671 eligible women, followed on average for 19.8 (SD 6.5) years, there were 58,134 incident breast cancers with known ER status and 40,627 with known surrogate molecular subtype (based on ER, PR, and HER2 status). Most established risk factors were primarily either positively (age at first birth, age at menopause, BMI, height, alcohol intake, and menopausal hormone therapy use) or inversely (parity) associated with ER+ cancer (p-value for heterogeneity by ER status < = 0.002 in each case). Only prior oral contraceptive (OC) use showed a greater association with ER than with ER+ cancer (p = 0.002). Some additional differences were observed by surrogate molecular subtype including a modest positive association of parity, and inverse association of breastfeeding, with the risk of basal-like cancer.

Conclusions: Most established risk factors for breast cancer are almost exclusively associated with hormone-sensitive cancers but some have definite associations with ER- cancers (prior OC use), or more specifically, with basal-like cancer (parity, breastfeeding).