Global Characterization of the SRC-1 Transcriptome Identifies ADAM22 as an ER-Independent Mediator of Endocrine-Resistant Breast Cancer

Endocrine Oncology Research, Department of Surgery, Royal College of Surgeons in Ireland, Dublin, Ireland.
Cancer Research (Impact Factor: 9.33). 11/2011; 72(1):220-9. DOI: 10.1158/0008-5472.CAN-11-1976
Source: PubMed


The development of breast cancer resistance to endocrine therapy results from an increase in cellular plasticity that permits the emergence of a hormone-independent tumor. The steroid coactivator protein SRC-1, through interactions with developmental proteins and other nonsteroidal transcription factors, drives this tumor adaptability. In this discovery study, we identified ADAM22, a non-protease member of the ADAM family of disintegrins, as a direct estrogen receptor (ER)-independent target of SRC-1. We confirmed SRC-1 as a regulator of ADAM22 by molecular, cellular, and in vivo studies. ADAM22 functioned in cellular migration and differentiation, and its levels were increased in endocrine resistant-tumors compared with endocrine-sensitive tumors in mouse xenograft models of human breast cancer. Clinically, ADAM22 was found to serve as an independent predictor of poor disease-free survival. Taken together, our findings suggest that SRC-1 switches steroid-responsive tumors to a steroid-resistant state in which the SRC-1 target gene ADAM22 has a critical role, suggesting this molecule as a prognostic and therapeutic drug target that could help improve the treatment of endocrine-resistant breast cancer.

Download full-text


Available from: Li Qin, Jul 28, 2015
  • Source
    • "Importantly, our results showed that higher levels of SRC-1 were predominantly detected in the PDC and MDC but not WDC, strongly indicating that SRC-1 could become a novel marker to identify different grading of chondrosarcoma as well as a poor prognostic factor for chondrosarcoma . Similar results were reported in human thyroid cancer [13] and breast cancers [31], since levels of SRC-1 was low in well-differentiated human thyroid cancer but increased in dedifferentiated cases [13]; and SRC-1 was proposed as a prognostic and therapeutic drug target or predictor of mammary cancer recurrence [31] [32]. Our results showed significant higher levels of SRC-3 in PDC and MDC but not WDC, these were also in well agreement with previous studies showing SRC-3 levels were related to tumor grade. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chondrosarcoma is the second most common type of primary bone malignancy following up osteosarcoma, characterized by resistance to conventional chemotherapeutic agents and radiation regimens. The p160 family members steroid receptor coactivator-1 and -3 (SRC-1 and SRC-3) have been implied in the regulation of cancer growth, migration, invasion, metastasis and chemotherapeutic resistance; but we still lack detail information about the levels of SRCs in chondrosarcoma. In this study, expression of SRC-1 and SRC-3 in chondrosarcoma was examined by immunohistochemistry with tissue microarrays; the four score system (0, 1, 2 and 3) was used to evaluate the staining. The results showed that there were no gender-, site- or age-differences regarding the expression of SRC-1 or SRC-3 (P > 0.05); organ (bone or cartilage) -differences were only detected for SRC-1 but not SRC-3 (p < 0.05). Significant higher levels of SRC-1 and SRC-3 were detected in MDC and PDC when compared to WDC. Our study clearly demonstrated differentiation-dependant expression of SRC-1 and SRC-3 in chondrosarcoma, may be novel targets for the prognosis and/or treatment of chondrosarcoma, would have opened a new avenue and established foundation for studying chondrosarcoma.
    Pathology - Research and Practice 05/2014; 210(12). DOI:10.1016/j.prp.2014.04.012 · 1.40 Impact Factor
  • Source
    • "In addition, expression of ADAM22 mRNA was increased in the Tamoxifen-resistant tumors in xenograft mouse models. Furthermore, ADAM22 expression was identified by immunohistochemical analysis in a clinical patient population as an independent predictor of poor disease free survival 107. ADAM22 has also been proposed as a potential therapeutic target as its migratory action can be inhibited following treatment with its ligand LGI1 107. "
    [Show abstract] [Hide abstract]
    ABSTRACT: In 1995, the steroid receptor coactivator-1 (SRC-1) was identified as the first authentic steroid receptor coactivator. Since then, the SRC proteins have remained at the epicenter of coregulator biology, molecular endocrinology and endocrine-related cancer. Cumulative works on SRC-1 have shown that it is primarily a nuclear receptor coregulator and functions to construct highly specific enzymatic protein complexes which can execute efficient and successful transcriptional activation of designated target genes. The versatile nature of SRC-1 enables it to respond to steroid dependent and steroid independent stimulation, allowing it to bind across many families of transcription factors to orchestrate and regulate complex physiological reactions. This review highlights the multiple functions of SRC-1 in the development and maintenance of normal tissue functions as well as its major role in mediating hormone receptor responsiveness. Insights from genetically manipulated mouse models and clinical data suggest SRC-1 is significantly overexpressed in many cancers, in particular, cancers of the reproductive tissues. SRC-1 has been associated with cellular proliferation and tumor growth but its major tumorigenic contributions are promotion and execution of breast cancer metastasis and mediation of resistance to endocrine therapies. The ability of SRC-1 to coordinate multiple signaling pathways makes it an important player in tumor cells' escape of targeted therapy.
    International journal of biological sciences 03/2012; 8(4):470-85. DOI:10.7150/ijbs.4125 · 4.51 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients.
    International Journal of Molecular Sciences 12/2012; 14(1):108-45. DOI:10.3390/ijms14010108 · 2.86 Impact Factor
Show more