Identifying new transcriptional targets for SRC-1 in breast cancer

SRC-1 is a p160 nuclear receptor co-activator protein that has been implicated as an important mediator of breast cancer metastasis. A small number of direct SRC-1 target genes have been identified to date. The aim of this work was to verify the recently discovered SRC-1 target SlOOB and to adopt a genome wide approach using modern, high throughput technologies to identify new SRC-1 transcriptional targets. To identify novel SRC-1 target genes luminal B LY2 breast cancer cells were used to perform the first ChlP-sequencing experiment of SRC-1. Affymetrix whole genome expression arrays were used to analyse gene expression in LY2 cells treated with SRC-1 siRNA in comparison with those treated scrambled siRNA to complement the ChlP-seq experiment. SRC-1 peaks within the genome were focused near transcription starts sites and often in close proximity to an estrogen response element. Three new putative SRC-1 target genes were selected for further validation. ADAM22 is a transmembrane disintegrin protein that has been shown to mediate cell migration but has yet to be implicated in tumourigenesis. Knockout, overexpression and ChlP studies confirm ADAM22 as an SRC-1 target gene. Expression of ADAM22 was identified in 49% of patients with breast cancer and its expression was associated with an almost two fold increase in rate of disease relapse. Two other genes, namely BCAS3 and CUXl were identified and validated as SRC-1 target genes and both of these have a known role in breast tumour progression. Elevated levels of SlOOB were detectable in the blood of 10% of patients with breast cancer. Elevated serum SlOOB at time of diagnosis is an independent predictor of disease progression in breast cancer. An unbiased, genome wide approach has identified a variety of novel, direct SRC-1 target genes. A series of molecular and translational studies have validated SlOOB as a clinically important and detectable target of SRC-1 while ADAM22, as transmembrane protein may offer the first therapeutic target to disrupt the central role of SRC-1 in mediating breast cancer metastasis

Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer.

INTRODUCTION: HOX genes play vital roles in growth and development, however, atypical redeployment of these genes is often associated with steroidal adaptability in endocrine cancers. We previously identified HOXC11 to be an indicator of poor response to hormonal therapy in breast cancer. In this study we aimed to elucidate genes regulated by HOXC11 in the endocrine resistant setting. METHODS: RNA-sequencing paired with transcription factor motif-mapping was utilised to identify putative HOXC11 target genes in endocrine resistant breast cancer. Validation and functional evaluation of the target gene, prosaposin (PSAP), was performed in a panel of endocrine sensitive and resistant breast cancer cell lines. The clinical significance of this finding was explored in clinical cohorts at both mRNA and protein level. RESULTS: PSAP was shown to be regulated by HOXC11 in both tamoxifen and aromatase inhibitor (AI) resistant cell lines. Transcript levels of HOXC11 and PSAP correlated strongly in samples of primary breast tumours (r = 0.7692, n = 51). PSAP has previously been reported to activate androgen receptor (AR) in prostate cancer cells. In a panel of breast cancer cell lines it was shown that endocrine resistant cells exhibit innately elevated levels of AR compared to their endocrine sensitive counterparts. Here, we demonstrate that stimulation with PSAP can drive AR recruitment to a hormone response element (HRE) in AI resistant breast cancer cells. Functionally, PSAP promotes cell migration and invasion only in AI resistant cells and not in their endocrine sensitive counterparts. In a cohort of breast cancer patients (n = 34), elevated serum levels of PSAP were found to associate significantly with poor response to endocrine treatment (p = 0.04). Meta-analysis of combined PSAP and AR mRNA are indicative of poor disease-free survival in endocrine treated breast cancer patients (hazard ratio (HR): 2.2, P = 0.0003, n = 661). CONCLUSION: The HOXC11 target gene, PSAP, is an AR activator which facilitates adaptation to a more invasive phenotype in vitro. These findings have particular relevance to the development of resistance to AI therapy which is an emerging clinical issue. PSAP is a secreted biomarker which has potential in identifying patients failing to exhibit sustained response to hormonal treatment

The impact of immediate breast reconstruction on the time to delivery of adjuvant therapy: the iBRA-2 study

Background: Immediate breast reconstruction (IBR) is routinely offered to improve quality-of-life for women requiring mastectomy, but there are concerns that more complex surgery may delay adjuvant oncological treatments and compromise long-term outcomes. High-quality evidence is lacking. The iBRA-2 study aimed to investigate the impact of IBR on time to adjuvant therapy. Methods: Consecutive women undergoing mastectomy ± IBR for breast cancer July–December, 2016 were included. Patient demographics, operative, oncological and complication data were collected. Time from last definitive cancer surgery to first adjuvant treatment for patients undergoing mastectomy ± IBR were compared and risk factors associated with delays explored. Results: A total of 2540 patients were recruited from 76 centres; 1008 (39.7%) underwent IBR (implant-only [n = 675, 26.6%]; pedicled flaps [n = 105,4.1%] and free-flaps [n = 228, 8.9%]). Complications requiring re-admission or re-operation were significantly more common in patients undergoing IBR than those receiving mastectomy. Adjuvant chemotherapy or radiotherapy was required by 1235 (48.6%) patients. No clinically significant differences were seen in time to adjuvant therapy between patient groups but major complications irrespective of surgery received were significantly associated with treatment delays. Conclusions: IBR does not result in clinically significant delays to adjuvant therapy, but post-operative complications are associated with treatment delays. Strategies to minimise complications, including careful patient selection, are required to improve outcomes for patients

Pregnancy-associated breast cancer: does timing of presentation affect outcome?

PURPOSE: Pregnancy-associated breast cancer (PABC) comprises breast cancer diagnosed during the gestational period or within 12 months postpartum. While the incidence of PABC appears to be increasing, data regarding prognosis remain limited. METHODS: Here we evaluate clinicopathologic features, treatments, and clinical outcomes among women with stage 0-III PABC diagnosed between 1992 and 2020. Comparisons were made between women who were diagnosed with PABC during gestation and those who were diagnosed within 12 months postpartum. RESULTS: A total of 341 women were identified, with a median age of 36 years (range 25-46). The pregnancy group comprised 119 (35%) women, while 222 (65%) women made up the postpartum group. Clinicopathologic features were similar between groups, with most patients being parous and presenting with stage I and II disease. Treatment delays were uncommon, with a median time from histologic diagnosis to treatment of 4 weeks for both groups. Recurrence-free survival was similar between groups: 67% at 10 years for both. While 10-year overall survival appeared higher in the postpartum group (83% versus 78%, p = 0.02), only the presence of nodal metastases was associated with an increased risk of death (hazard ratio 5.61, 95% CI 2.20-14.3, p \u3c 0.001), whereas timing of diagnosis and receptor profile did not reach statistical significance. CONCLUSION: Clinicopathologic features of women with PABC are similar regardless of timing of diagnosis. While 10-year recurrence-free survival is similar between groups, 10-year overall survival is higher among women diagnosed postpartum; however, timing of diagnosis may not be the driving factor in determining survival outcomes

Rabbinic Elements in the Verbal System of Maskilic Hebrew Fiction 1857-1881

a Hazard ratio (HR) curve was generated for prosaposin (PSAP) using the TCGA dataset. PSAP expressions between 25 and 75 % quantiles have a HR consistently >1. b Androgen receptor (AR) mRNA does not associate with poor disease-free survival (DFS) in endocrine-treated breast cancer. Kaplan-Meier survival curves were generated to assess the impact of high androgen receptor transcript levels on survival of endocrine-treated patients with breast cancer (n = 661). (PDF 204 kb

Additional file 6: of Prosaposin activates the androgen receptor and potentiates resistance to endocrine treatment in breast cancer

Table: Estrogen receptor (ER) motif results ( p <0.001). A 400-bp-sized window surrounding starting sites of HOXC11 target genes was selected for ER motif searching. The searching process was performed using the FIMO program available in MEME-suite with the p value significant cutoff set at 0.001. (PDF 198 kb