Non-Genomic Androgen Action Regulates Proliferative/Migratory Signaling in Stromal Cells

Donato, Marzia Di; Giovannelli, Pia; Cernera, Gustavo; Santi, Annalisa Di; Marino, Irene; Bilancio, Antonio; Galasso, Giovanni; Auricchio, Ferdinando; Migliaccio, Antimo; Castoria, Gabriella

doi:10.3389/fendo.2014.00225

Cited by 32 publications

(31 citation statements)

References 38 publications

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“…In accordance with previous reports in prostate cancer fibroblasts [24], we observed that AR is expressed in breast cancer stromal cells. Although there are indications that high AR levels may be associated with response to chemotherapy [18], stromal AR mRNA was not differentially expressed in DS vs. NDS samples.…”

Section: Discussionsupporting

confidence: 93%

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

Katayama

Vieira

Andrade

et al. 2019

Cells

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Breast cancer stromal compartment, may influence responsiveness to chemotherapy. Our aim was to detect a stromal cell signature (using a direct approach of microdissected stromal cells) associated with response to neoadjuvant chemotherapy (neoCT) in locally advanced breast cancer (LABC). The tumor samples were collected from 44 patients with LABC (29 estrogen receptor (ER) positive and 15 ER negative) before the start of any treatment. Neoadjuvant chemotherapy consisted of doxorubicin and cyclophosphamide, followed by paclitaxel. Response was defined as downstaging to maximum ypT1a-b/ypN0. The stromal cells, mainly composed of fibroblast and immune cells, were microdissected from fresh frozen tumor samples and gene expression profile was determined using Agilent SurePrint G3 Human Gene Expression microarrays. Expression levels were compared using MeV (MultiExperiment Viewer) software, applying SAM (significance analysis of microarrays). To classify samples according to tumor response, the order of median based on confidence statements (MedOr) was used, and to identify gene sets correlated with the phenotype downstaging, gene set enrichment analysis (GSEA). Nine patients presented disease downstaging. Eleven sequences (FDR 17) were differentially expressed, all of which (except H2AFJ) more expressed in responsive tumors, including PTCHD1 and genes involved in abnormal cytotoxic T cell physiology, TOX, LY75, and SH2D1A. The following four pairs of markers could correctly classify all tumor samples according to response: PTCHD1/PDXDC2P, LOC100506731/NEURL4, SH2D1A/ENST00000478672, and TOX/H2AFJ. Gene sets correlated with tumor downstaging (FDR < 0.01) were mainly involved in immune response or lymphocyte activation, including CD47, LCK, NCK1, CD24, CD3E, ZAP70, FOXP3, and CD74, among others. In locally advanced breast cancer, stromal cells may present specific features of immune response that may be associated with chemotherapy response.

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Section: Discussionsupporting

confidence: 93%

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

Katayama

Vieira

Andrade

et al. 2019

Cells

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“…Studies in prostate cancer have reported on many mechanisms of rapid non genomic 2nd messenger signaling following exposure to androgens ( 117 , 118 ). Furthermore, non-genomic AR signaling has been reported in the sertoli cells of the testes ( 119 ), fibroblasts ( 106 ), osteoblasts and osteocytes ( 120 ), stromal cells ( 121 ), and breast cancer cells. ERα and AR have been shown to directly interact with the SH2 and SH3 domain respectively of Src.…”

Section: Ar Localization Non-genomic Signaling and Functional Conseqmentioning

confidence: 99%

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Bleach

McIlroy

2018

Front. Endocrinol.

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Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19–29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.

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“…These cells have, in most cases, been considered androgen insensitive because of their very low AR expression level, and hence the absence of AR-mediated gene transcription. Nonetheless, they still respond to androgens with activation of signaling effectors [ 105 ]. Moreover, the findings so far reported on AR expression in prostate SCs or CSCs do not exclude that membrane AR might be expressed in these cells.…”

Section: Ar In Prostate Scs and Cscsmentioning

confidence: 99%

Prostate cancer stem cells: the role of androgen and estrogen receptors

et al. 2015

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Prostate cancer is one of the most commonly diagnosed cancers in men, and androgen deprivation therapy still represents the primary treatment for prostate cancer patients. This approach, however, frequently fails and patients develop castration-resistant prostate cancer, which is almost untreatable.Cancer cells are characterized by a hierarchical organization, and stem/progenitor cells are endowed with tumor-initiating activity. Accumulating evidence indicates that prostate cancer stem cells lack the androgen receptor and are, indeed, resistant to androgen deprivation therapy. In contrast, these cells express classical (α and/or β) and novel (GPR30) estrogen receptors, which may represent new putative targets in prostate cancer treatment.In the present review, we discuss the still-debated mechanisms, both genomic and non-genomic, by which androgen and estradiol receptors (classical and novel) mediate the hormonal control of prostate cell stemness, transformation, and the continued growth of prostate cancer. Recent preclinical and clinical findings obtained using new androgen receptor antagonists, anti-estrogens, or compounds such as enhancers of androgen receptor degradation and peptides inhibiting non-genomic androgen functions are also presented. These new drugs will likely lead to significant advances in prostate cancer therapy.

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Non-Genomic Androgen Action Regulates Proliferative/Migratory Signaling in Stromal Cells

Cited by 32 publications

References 38 publications

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

Stromal Cell Signature Associated with Response to Neoadjuvant Chemotherapy in Locally Advanced Breast Cancer

The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Prostate cancer stem cells: the role of androgen and estrogen receptors

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