Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide <i>In Vivo</i>

Barton, Valerie N.; D’Amato, Nicholas C.; Gordon, Michael A.; Lind, Hanne; Spoelstra, Nicole S.; Babbs, Beatrice; Heinz, Richard E.; Elias, Anthony; Jedlicka, Paul; Jacobsen, Britta M.; Richer, Jennifer K.

doi:10.1158/1535-7163.mct-14-0926

Cited by 189 publications

(210 citation statements)

References 43 publications

(60 reference statements)

Supporting

Mentioning

187

Contrasting

Unclassified

Order By: Relevance

“…While this manuscript was in preparation, Barton and coworkers reported the anti-proliferative effects of enzalutamide in four TNBC cell lines (Barton et al 2015). In contrast, our study investigated the potential growth inhibitory effects of enzalutamide in 11 cell lines (eight of which were TN) and flutamide in four cell lines (all TN).…”

Section: Discussionmentioning

confidence: 91%

“…Because of the absence of these three predictive biomarkers, TNBC currently lacks a validated targeted therapy (Duffy et al 2012). Although lacking ER, PR and HER2, approximately 22-45% of TNBC express AR (Gucalp & Traina 2010, Park et al 2010, Kotsopoulos & Narod 2012, McNamara et al 2013, Gasparini et al 2014, Safarpour & Tavassoli 2014, Barton et al 2015.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

The androgen receptor (AR) is present in approximately 80% of invasive breast cancer patients and in up to 30% of patients with triple-negative breast cancer (TNBC). Therefore, our aim was to investigate the targeting of AR as a possible hormonal approach to the treatment of TNBC. Analysis of 2091 patients revealed an association between AR expression and poor overall survival, selectively in patients with the basal subtype of breast cancer, the vast majority of which are TNBC. IC 50 values for the secondgeneration anti-androgen enzalutamide across 11 breast cancer cell lines varied from 4 µM to >50 µM. The activity of enzalutamide was similar in TN and non-TN cell lines but was dependent on the presence of AR. Enzalutamide reduced clonogenic potential and cell growth in a 3D matrix in AR-positive cells. In addition, enzalutamide also inhibited cell migration and invasion in an AR-dependent manner. Enzalutamide appeared to mediate these processes through down-regulation of the transcription factors AP-1 and SP-1. The first-generation anti-androgen flutamide similarly blocked cell growth, migration and invasion. AR-positive TNBC cells clustered separately from AR-negative cells based on an androgen-related gene expression signature, independently of TNBC subtype. We conclude that targeting of the AR with drugs such as enzalutamide may provide an alternative treatment strategy for patients with AR-positive TNBC.

show abstract

Section: Discussionmentioning

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Caiazza¹,

Murray²,

Madden³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

show abstract

“…TNBC (ER/PR-negative and HER2-negative) can be divided into different subtypes on the basis of the gene expression signature, that is, basal-like 1 and 2 subtypes enriched in cell cycle and DNA damage response components and pathways; immunomodulatory subtype enriched for gene ontologies in immune cell processes; mesenchymal and mesenchymal stem-like subtypes enriched in components and pathways involved in cell motility, epithelial-mesenchymal transition and growth factor pathways; luminal AR (LAR) subtype (previously characterized as molecular apocrine subtype) with a gene expression profile mimicking luminal subtypes despite being ER-negative and enriched in hormonally regulated pathways including steroid synthesis (high AR expression) (Lehmann et al 2011, Barton et al 2015.…”

Section: Figurementioning

confidence: 99%

“…Preclinical data suggest that AR drives tumor progression in some subtypes of TNBC (Barton et al 2015, Chia et al 2015. In particular, in vitro studies show that AR activation can reduce chemotherapy efficacy in LAR subtype through the AR-mediated transcriptional regulation of pro-and anti-apoptotic genes (Pang et al 2006), suggesting the usefulness of an AR block combined with chemotherapy in this setting (Kach et al 2015).…”

Section: Figurementioning

confidence: 99%

Androgen receptor signaling pathways as a target for breast cancer treatment

Pietri¹,

Conteduca²,

Andreis³

et al. 2016

Endocrine-Related Cancer

View full text Add to dashboard Cite

The androgen receptor (AR) is a ligand-dependent transcription factor, and its effects on breast range from physiological pubertal development and age-related modifications to cancer onset and proliferation. The prevalence of AR in early breast cancer is around 60%, and AR is more frequently expressed in ER-positive than in ER-negative tumors. We offer an overview of AR signaling pathways in different breast cancer subtypes, providing evidence that its oncogenic role is likely to be different in distinct biological and clinical scenarios. In particular, in ER-positive breast cancer, AR signaling often antagonizes the growth stimulatory effect of ER signaling; in triple-negative breast cancer (TNBC), AR seems to drive tumor progression (at least in luminal AR subtype of TNBC with a gene expression profile mimicking luminal subtypes despite being negative to ER and enriched in AR expression); in HER2-positive breast cancer, in the absence of ER expression, AR signaling has a proliferative role. These data represent the rationale for AR-targeting treatment as a potentially new target therapy in breast cancer subset using androgen agonists in some AR-positive/ER-positive tumors, AR antagonists in triple-negative/ AR-positive tumors and in combination with anti-HER2 agents or with other signaling pathways inhibitors (including PI3K/MYC/ERK) in HER2-positive/AR-positive tumors. Only the ongoing and future prospective clinical trials will allow us to establish which agents are the best option in every specific condition, keeping in mind that there is evidence of opposite androgens and AR agonist/antagonist drug effects on cell proliferation particularly in AR-positive/ER-positive tumors.

show abstract

“…That study showed that only 1% of tumor cells in a TNBC must be AR þ to show benefit from ARtargeted therapies. 44 In addition, multiple clinical trials currently underway for patients with TNBC have shown promising preliminary results with AR-targeted therapies against TNBCs with a higher percentage of AR þ cells. 45 We, therefore, propose testing for AR expression in all metastatic/recurrent TNBCs and primary TNBCs that do not completely respond to chemotherapy to help guide management decisions.…”

Section: Prognostic and Predictive Values Of Androgen Receptor In Tnbcsmentioning

confidence: 99%

Update on Immunohistochemical Analysis in Breast Lesions

Peng¹,

Butt²,

Chen³

et al. 2017

Archives of Pathology &Amp; Laboratory Medicine

View full text Add to dashboard Cite

Context.-The utility of immunohistochemistry (IHC) in breast lesions needs to be updated with exceptions among these lesions. Biomarker studies with IHC in triple-negative breast carcinoma may help develop targeted therapies for this aggressive breast cancer. The distinction of metastatic lung adenocarcinoma to the breast and invasive breast carcinoma has significant prognostic and therapeutic implications. The determination can be challenging because both primary tumors can express estrogen receptor and/or HER2 by IHC, creating a diagnostic dilemma.Objectives.-To provide a practical update on the use of IHC markers in differential diagnoses in breast lesions, including benign, atypical, precancerous, and malignant tumors; to highlight recently published research findings on novel IHC markers in triple-negative breast carcinoma cases; and to reinforce the importance of IHC use as an ancillary tool in distinguishing metastatic lung adenocarcinoma to the breast from primary breast carcinoma using real case examples.Data Sources.-PubMed (US National Library of Medicine, Bethesda, Maryland) literature review and authors' research data and personal experiences were used in this review.Conclusions.-Immunohistochemistry has an important role in making differential diagnoses in breast lesions in morphologically equivocal settings; recognizing IHC expression status in the exceptions among these lesions will aid in the correct diagnosis of challenging breast cases. Studies suggest that androgen receptor, p16, p53, GATA3, and PELP1 may have potential diagnostic, prognostic, and predictive value in triple-negative breast carcinoma cases; these findings may provide insight and a greater understanding of the tumor biology in triple-negative breast carcinomas. In distinguishing metastatic estrogen receptor-positive or HER2 þ lung adenocarcinoma to the breast from primary breast carcinoma, napsin A, TTF-1, and GATA3 comprise a useful IHC panel.

show abstract

Multiple Molecular Subtypes of Triple-Negative Breast Cancer Critically Rely on Androgen Receptor and Respond to Enzalutamide In Vivo

Cited by 189 publications

References 43 publications

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Preclinical evaluation of the AR inhibitor enzalutamide in triple-negative breast cancer cells

Androgen receptor signaling pathways as a target for breast cancer treatment

Update on Immunohistochemical Analysis in Breast Lesions

Contact Info

Product

Resources

About