High-Risk Breast Lesions

It is well known that certain types of pre-malignant lesions can predispose some women to increased risk of breast cancer. These certain types of pre-malignant lesions are generally classified as high-risk breast lesions. These lesions become invasive cancers in about 15% of patients and hence the management and treatment of these lesions warrant a significant discussion. There are several categories of these lesions, to include atypical hyperplasia of the breast (atypical ductal hyperplasia and atypical lobular hyperplasia); carcinoma in situ (ductal carcinoma in situ and lobular carcinoma in situ); columnar cell pre-malignant lesions; lobular intraepithelial neoplasia (LIN III); radial scar/complex sclerosing lesion; sclerosing adenosis and papillary lesions of the breast. These lesions are morphologically, radiologically, histologically and clinically heterogeneous and early identification can help to prevent progression to invasive cancers. The management of these lesions has been debated internationally for years by experts as to the best treatment modality with surgical excision of the lesion often not considered necessary. It is thus important to evaluate each patient on an individual case-by-case basis. The characteristics of these high-risk breast lesions are further discussed in this chapter

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

HOXC11 impacts steroidal adaptability in aromatase inhibitor resistance by up-regulating the androgen receptor

Introduction Aromatase Inhibitors (AI) are the gold-standard treatment of postmenopausal breast cancer. They inhibit the conversion of androgens to estrone by CYP19 thereby blocking ligand-dependent activation of the estrogen receptor (ER). Research from our lab has identified the homeobox protein, HOXC11, as an indicator of poor response to endocrine therapy and metastases development. We aim to investigate the role of the HOXC11 target gene prosaposin (PSAP) in aromatase inhibitor resistance and assess the impact of PSAP and androgen receptor (AR) on clinical outcome. Methods RNA-sequencing was performed to identify HOXC11 target genes in endocrine-resistant breast cancer. Molecular biology techniques were used to validate these findings. Statistical analysis (STATA10) was used to ascertain the impact of these genes on survival rates in a cohort of breast cancer patients (n = 488). Results PSAP was shown to be the most significant target gene regulated by HOXC11. PSAP up-regulates AR protein expression. Down-regulation of AR reduced cell proliferation and motility in AI resistant cells. Treatment with a recombinant PSAP protein (rhPSAP) increased cell migration and invasion. Survival analysis of breast cancer patients (n = 488) showed that the intensity of AR IHC staining (> score 1) was found to inversely associate with recurrence (**p Conclusion HOXC11 up-regulates PSAP which promotes AR expression in AI resistance. This elucidates a novel mechanism enabling tumour utilisation of androgens for cell proliferation. AR expression is usually associated with good survival in breast cancer; however, in the AI treated population this is not the case. Thus, AR antagonists could have efficacy in treating refractory disease either alone or in combination with PI3K/mTOR inhibitors with serum secreted PSAP as potential indicator for the development of endocrine resistance and as a predictor of poor DFS.</p

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