Estrogen receptor mutations and their role in breast cancer progression

Abstract Endocrine therapy is the mainstay of treatment in estrogen receptor-positive breast cancers and significantly reduces disease recurrence and breast cancer-related mortality. However, acquired resistance to therapy has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. Mutations in the estrogen receptor have long been speculated to play a role in endocrine therapy resistance but have been rarely detected. However, recent studies utilizing next-generation sequencing on estrogen receptor-positive, metastatic clinical samples have revealed that recurrent ESR1 mutations are far more frequent than previously thought and may play an important role in acquired endocrine therapy resistance. Here we review recent advances in detection and characterization of ESR1 mutations in advanced, endocrine therapy-resistant breast cancers.https://deepblue.lib.umich.edu/bitstream/2027.42/137677/1/13058_2014_Article_494.pd

Androgen receptor as a mediator and biomarker of radioresistance in triple-negative breast cancer.

Increased rates of locoregional recurrence have been observed in triple-negative breast cancer despite chemotherapy and radiation therapy. Thus, approaches that combine therapies for radiosensitization in triple-negative breast cancer are critically needed. We characterized the radiation therapy response of 21 breast cancer cell lines and paired this radiation response data with high-throughput drug screen data to identify androgen receptor as a top target for radiosensitization. Our radiosensitizer screen nominated bicalutamide as the drug most effective in treating radiation therapy-resistant breast cancer cell lines. We subsequently evaluated the expression of androgen receptor in >2100 human breast tumor samples and 51 breast cancer cell lines and found significant heterogeneity in androgen receptor expression with enrichment at the protein and RNA level in triple-negative breast cancer. There was a strong correlation between androgen receptor RNA and protein expression across all breast cancer subtypes (R2 = 0.72, p < 0.01). In patients with triple-negative breast cancer, expression of androgen receptor above the median was associated with increased risk of locoregional recurrence after radiation therapy (hazard ratio for locoregional recurrence 2.9-3.2)) in two independent data sets, but there was no difference in locoregional recurrence in triple-negative breast cancer patients not treated with radiation therapy when stratified by androgen receptor expression. In multivariable analysis, androgen receptor expression was most significantly associated with worse local recurrence-free survival after radiation therapy (hazard ratio of 3.58) suggesting that androgen receptor expression may be a biomarker of radiation response in triple-negative breast cancer. Inhibition of androgen receptor with MDV3100 (enzalutamide) induced radiation sensitivity (enhancement ratios of 1.22-1.60) in androgen receptor-positive triple-negative breast cancer lines, but did not affect androgen receptor-negative triple-negative breast cancer or estrogen-receptor-positive, androgen receptor-negative breast cancer cell lines. androgen receptor inhibition with MDV3100 significantly radiosensitized triple-negative breast cancer xenografts in mouse models and markedly delayed tumor doubling/tripling time and tumor weight. Radiosensitization was at least partially dependent on impaired dsDNA break repair mediated by DNA protein kinase catalytic subunit. Our results implicate androgen receptor as a mediator of radioresistance in breast cancer and identify androgen receptor inhibition as a potentially effective strategy for the treatment of androgen receptor-positive radioresistant tumors

The lncRNA landscape of breast cancer reveals a role for DSCAM-AS1 in breast cancer progression.

Molecular classification of cancers into subtypes has resulted in an advance in our understanding of tumour biology and treatment response across multiple tumour types. However, to date, cancer profiling has largely focused on protein-coding genes, which comprise <1% of the genome. Here we leverage a compendium of 58,648 long noncoding RNAs (lncRNAs) to subtype 947 breast cancer samples. We show that lncRNA-based profiling categorizes breast tumours by their known molecular subtypes in breast cancer. We identify a cohort of breast cancer-associated and oestrogen-regulated lncRNAs, and investigate the role of the top prioritized oestrogen receptor (ER)-regulated lncRNA, DSCAM-AS1. We demonstrate that DSCAM-AS1 mediates tumour progression and tamoxifen resistance and identify hnRNPL as an interacting protein involved in the mechanism of DSCAM-AS1 action. By highlighting the role of DSCAM-AS1 in breast cancer biology and treatment resistance, this study provides insight into the potential clinical implications of lncRNAs in breast cancer

Functional proteomics can define prognosis and predict pathologic complete response in patients with breast cancer

<p>Abstract</p> <p>Purpose</p> <p>To determine whether functional proteomics improves breast cancer classification and prognostication and can predict pathological complete response (pCR) in patients receiving neoadjuvant taxane and anthracycline-taxane-based systemic therapy (NST).</p> <p>Methods</p> <p>Reverse phase protein array (RPPA) using 146 antibodies to proteins relevant to breast cancer was applied to three independent tumor sets. Supervised clustering to identify subgroups and prognosis in surgical excision specimens from a training set (n = 712) was validated on a test set (n = 168) in two cohorts of patients with primary breast cancer. A score was constructed using ordinal logistic regression to quantify the probability of recurrence in the training set and tested in the test set. The score was then evaluated on 132 FNA biopsies of patients treated with NST to determine ability to predict pCR.</p> <p>Results</p> <p>Six breast cancer subgroups were identified by a 10-protein biomarker panel in the 712 tumor training set. They were associated with different recurrence-free survival (RFS) (log-rank p = 8.8 E-10). The structure and ability of the six subgroups to predict RFS was confirmed in the test set (log-rank p = 0.0013). A prognosis score constructed using the 10 proteins in the training set was associated with RFS in both training and test sets (p = 3.2E-13, for test set). There was a significant association between the prognostic score and likelihood of pCR to NST in the FNA set (p = 0.0021).</p> <p>Conclusion</p> <p>We developed a 10-protein biomarker panel that classifies breast cancer into prognostic groups that may have potential utility in the management of patients who receive anthracycline-taxane-based NST.</p

A novel role for TTK in homologous recombination: implications for breast cancer radiosensitivity

Basal-like breast cancers have the highest rates of locoregional recurrence after radiation. By correlating gene expression with early locoregional recurrence, we nominate TTK protein kinase as a mediator of radioresistance. TTK inhibition radiosensitizes in vitro and in vivo through a novel mechanism of impaired homologous recombination and represents a promising translational strategy

Molecular Signatures of Radiation Response in Breast Cancer: Towards Personalized Decision-Making in Radiation Treatment

Recent advances in gene expression profiling have allowed for a more sophisticated understanding of the biology of breast cancers. These advances led to the development of molecular signatures that now allow clinicians to more individually tailor recommendations regarding the utility and necessity of systemic therapies for women with breast cancer. Indeed, these molecularly based tests have been incorporated into national and international best practice guidelines and are now part of routine practice. Similar, though slower, progress is being made in the development of molecular signatures predictive of radiation response and necessity for women with breast cancer. This article will discuss the history of radiation response signature development, the current state of these signatures under ongoing clinical development, the barriers to their clinical adoption, and upcoming changes and opportunities that may allow for the personalized radiation treatment recommendations enabled by the development of these signatures