WNT signalling in prostate cancer

Murillo-Garzón, Virginia; Kypta, Robert M.

doi:10.1038/nrurol.2017.144

Cited by 292 publications

(259 citation statements)

References 169 publications

(156 reference statements)

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“…Since growth and progression of PCa have previously been linked to developmental signals gone awry, we herein investigated whether the antiproliferative and prostemness roles for WNT10B during development might be co‐opted in a manner that promotes PCa growth and/or progression including metastasis. Indeed, in the probasin/TAg rat prostate adenocarcinoma model, Wnt10b expression was reduced over 25‐fold while WNT10B protein was lost in the tumors concomitant with hyperproliferation at those sites which suggest that loss of WNT10B and its antiproliferative effects may contribute to uncontrolled growth of the cancerous cells.…”

Section: Discussionmentioning

confidence: 99%

“…33 In contrast, WNT10B expression inhibited the in vitro proliferation of erythroid progenitor cells underscoring the difference in activity of this ligand depending on cellular context. 33 Since growth and progression of PCa have previously been linked to developmental signals gone awry, [7][8][9] we herein investigated whether the antiproliferative and prostemness roles for WNT10B during development cells when the elevated WNT10B levels seen in metastatic cells are reduced. Inasmuch as the mechanism of EMT is still contested, there is more agreement that it is a necessary process to promote metastasis and this ability is likely conferred by stem-like properties in a subset of cancer cells.…”

Section: But Contrasts With Stromalmentioning

confidence: 99%

“…McNeal proposed in 1978 that benign prostatic hyperplasia was a result of adult prostate stroma regaining a molecular signature similar to the embryonic prostatic mesenchyme and coined the phrase “embryonic reawakening potential” for adult prostatic disease. Prostate cancer (PCa), the most diagnosed noncutaneous male malignancy in the United States and second leading cause of cancer‐related deaths in males, is also driven by the reawakening of developmental signals . Although radical prostatectomy has a significant impact on patient survival in cases of localized cancer, a significant number of patients require additional treatment for local recurrence and previously undiagnosed metastatic lesions .…”

Section: Introductionmentioning

confidence: 99%

“…Prostate cancer (PCa), the most diagnosed noncutaneous male malignancy in the United States and second leading cause of cancer-related deaths in males, is also driven by the reawakening of developmental signals. 8,9 Although radical prostatectomy has a significant impact on patient survival in cases of localized cancer, a significant number of patients require additional treatment for local recurrence and previously undiagnosed metastatic lesions. 10 Since PCa is initially androgen-dependent, the current mainstay of treatment for locally advanced PCa or metastatic disease consists of surgical or chemical castration resulting in androgen ablation and consequent tumor regression.…”

Section: Introductionmentioning

confidence: 99%

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The role of WNT10B in normal prostate gland development and prostate cancer

Madueke

et al. 2019

The Prostate

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Background WNT signaling is implicated in embryonic development, and in adult tissue homeostasis, while its deregulation is evident in disease. This study investigates the unique roles of canonical WNT10B in both normal prostate development and prostate cancer (PCa) progression. Methods Organ culture and rat ventral prostates (VPs) were used to study Wnt10b ontogeny and growth effect of WNT10B protein. PB‐SV40 LTag rat VPs were utilized for Wnt expression polymerase chain reaction (PCR) array and immunohistochemistry. Human localized PCa tissue microarrays (TMAs) were investigated for differential WNT10B expression. Human RNA‐seq data sets were queried for differential expression of WNT10B in metastatic and localized PCa. Knockdown of WNT10B in PC3 cells was utilized to study its effects on proliferation, stemness, epithelial to mesenchymal transition (EMT), and xenograft propagation. Results Wnt10b expression was highest at birth and rapidly declined in the postnatal rat VP. Exogenous WNT10B addition to culture developing VPs decreased growth suggesting an antiproliferative role. VPs from PB‐SV40 LTag rats with localized PCa showed a 25‐fold reduction in Wnt10b messenger RNA (mRNA) expession, confirmed at the protein level. Human PCa TMAs revealed elevated WNT10B protein in prostate intraepithelial neoplasia compared with normal prostates but reduced levels in localized PCa specimens. In contrast, RNA‐seq data set of annotated human PCa metastasis found a significant increase in WNT10B mRNA expression compared with localized tumors suggesting stage‐specific functions of WNT10B. Similarly, WNT10B mRNA levels were increased in metastatic cell lines PC3, PC3M, as well as in HuSLC, a PCa stem‐like cell line, as compared with disease‐free primary prostate epithelial cells. WNT10B knockdown in PC3 cells reduced expression of EMT genes, MMP9 and stemness genes NANOG and SOX2 and markedly reduced the stem cell‐like side population. Furthermore, loss of WNT10B abrogated the ability of PC3 cells to propagate tumors via serial transplantation. Conclusions Taken together, these results suggest a dual role for WNT10B in normal development and in PCa progression with opposing functions depending on disease stage. We propose that decreased WNT10B levels in localized cancer allow for a hyperproliferative state, whereas increased levels in advanced disease confer a stemness and malignant propensity which is mitigated by knocking down WNT10B levels. This raises the potential for WNT10B as a novel target for therapeutic intervention in metastatic PCa.

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Section: Discussionmentioning

confidence: 99%

Section: But Contrasts With Stromalmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The role of WNT10B in normal prostate gland development and prostate cancer

Madueke

et al. 2019

The Prostate

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“…CTNNB1 encodes for beta-catenin (β-catenin) and mediates the canonical WNT pathway regulation of cell fate and tissue development52 . WNT-β-catenin signaling promotes tumor progression, stem cell proliferation and treatment resistance in BCa53 and PCa54 . FGF2 signaling regulates normal tissue development, angiogenesis, and wound healing55 and FGF2 promotes tumor progression, metastasis, and/or angiogenesis in BCa 56 and PCa 57 .…”

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confidence: 99%

IL-1-conferred gene expression pattern in ERα⁺ BCa and AR⁺ PCa cells is intrinsic to ERα⁻ BCa and AR⁻ PCa cells and promotes cell survival

Nawas¹,

Kanchwala

Thomas‐Jardin

et al. 2019

Preprint

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Background: Breast (BCa) and prostate (PCa) cancers are hormone receptor (HR)-driven cancers. Thus, BCa and PCa patients are given therapies that reduce hormone levels or directly blocks HR activity; but most patients eventually develop treatment resistance. We have previously reported that interleukin-1 (IL-1) inflammatory cytokine downregulates ERα and AR mRNA in HR-positive (HR + ) BCa and PCa cell lines, yet the cells can remain viable. Additionally, we identified pro-survival proteins and processes upregulated by IL-1 in HR + BCa and PCa cells, that are basally high in HR -BCa and PCa cells. Therefore, we hypothesize that IL-1 confers a conserved gene expression pattern in HR + BCa and PCa cells that mimics conserved basal gene expression patterns in HR -BCa and PCa cells to promote HR-independent survival and tumorigenicity. Methods:We performed RNA sequencing (RNA-seq) for HR + BCa and PCa cell lines exposed to IL-1 and for untreated HR -BCa and PCa cell lines. We confirmed expression patterns of select genes by RT-qPCR and used siRNA and/or drug inhibition to silence select genes in HR -BCa cell lines. Finally, we performed Ingenuity Pathway Analysis (IPA) to identify signaling pathways encoded by our RNA-seq data set. Results:We identified 350 genes in common between BCa and PCa cells that are induced or repressed by IL-1 in HR + cells that are, respectively, basally high or low in HRcells. Among these genes, we identified Sequestome-1 (SQSTM1/p62) and SRY (Sex-Determining Region Y)-Box 9 (SOX9) to be essential for survival of HR -BCa and PCa cell lines. Analysis of publicly available data indicates that p62 and SOX9 expression are elevated in HR-independent BCa and PCa sublines generated in vitro, suggesting that p62 and SOX9 have a role in acquired treatment resistance. We also assessed HRcell line viability in response to the p62-targeting drug, verteporfin, and found that verteporfin is cytotoxic for HRcell lines. Conclusions:Our 350 gene set can be used to identify novel therapeutic targets and/or biomarkers conserved among acquired (e.g. due to inflammation) or intrinsic HR-independent BCa and PCa. BACKGROUND: Breast (BCa) and prostate (PCa) cancer share similar etiology, where hormone receptors (HR) drive cancer cell survival 1,2 . Estrogen Receptor Alpha (ERα) promotes BCa tumor growth and Androgen Receptor (AR) promotes PCa tumor growth; thus, patients are treated with HR-targeting therapies. Unfortunately, patients can become treatment resistant due to loss of HR dependence. For example, ≥ 30% of patients that develop metastatic, castration-resistant PCa have AR-negative (AR -) tumors 3 and 15-30% of BCa patients that develop endocrine resistance have tumors with reduced or lost ERα accumulation 1,4 . In addition, at the time of

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Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets

et al. 2021

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Both oncogenic and tumor suppressor functions have been described for junction plakoglobin (JUP), also known as c-catenin. To clarify the role of JUP in prostate cancer, JUP protein expression was immunohistochemically detected in a tissue microarray containing 11 267 individual prostatectomy specimens. Considering all patients, high JUP expression was associated with adverse tumor stage (P = 0.0002), high Gleason grade (P < 0.0001), and lymph node metastases (P = 0.011). These associations were driven mainly by the subset without TMPRSS2:ERG fusion, in which high JUP expression was an independent predictor of poor prognosis (multivariate analyses, P = 0.0054) and early biochemical recurrence (P = 0.0003). High JUP expression was further linked to strong androgen receptor expression (P < 0.0001), high cell proliferation, and PTEN and FOXP1 deletion (P < 0.0001). In the ERG-negative subset, high JUP expression was additionally linked to MAP3K7 (P = 0.0007) and CHD1 deletion (P = 0.0021). Contrasting the overall prognostic effect of JUP, low JUP expression indicated poor prognosis in the fraction of CHD1-deleted patients (P = 0.039). In this subset, the association of high JUP and high cell proliferation was specifically absent. In conclusion, the controversial biological roles of JUP are reflected by antagonistic prognostic effects in distinct prostate cancer patient subsets.

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WNT signalling in prostate cancer

Cited by 292 publications

References 169 publications

The role of WNT10B in normal prostate gland development and prostate cancer

The role of WNT10B in normal prostate gland development and prostate cancer

IL-1-conferred gene expression pattern in ERα⁺ BCa and AR⁺ PCa cells is intrinsic to ERα⁻ BCa and AR⁻ PCa cells and promotes cell survival

Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets

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WNT signalling in prostate cancer

Cited by 292 publications

References 169 publications

The role of WNT10B in normal prostate gland development and prostate cancer

The role of WNT10B in normal prostate gland development and prostate cancer

IL-1-conferred gene expression pattern in ERα+ BCa and AR+ PCa cells is intrinsic to ERα− BCa and AR− PCa cells and promotes cell survival

Opposing prognostic relevance of junction plakoglobin in distinct prostate cancer patient subsets

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IL-1-conferred gene expression pattern in ERα⁺ BCa and AR⁺ PCa cells is intrinsic to ERα⁻ BCa and AR⁻ PCa cells and promotes cell survival