Cooperativity of
            <i>Nkx3.1</i>
            and
            <i>Pten</i>
            loss of function in a mouse model of prostate carcinogenesis

Kim, Minjung; Cardiff, Robert D.; Desai, Nishita; Banach‐Petrosky, Whitney; Parsons, Ramon; Shen, Michael M.; Abate‐Shen, Cory

doi:10.1073/pnas.042688999

Cited by 293 publications

(311 citation statements)

References 31 publications

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“…Given that individual CE-metabolizing genes participate cooperatively in CE metabolism 11 and that an increased risk of cancer due to a combined effect of genes belonging to a common antitumor pathway has been demonstrated in a mouse model, 36 we examined whether a joint effect of these CE-metabolizing genes was associated with breast cancer development by determining the breast cancer risk associated with harboring different numbers of putative high-risk genotypes (Fig. 1).…”

Section: Resultsmentioning

confidence: 99%

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Cheng

Chen

Huang

et al. 2004

Intl Journal of Cancer

102

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Estrogen has been suggested to trigger breast cancer development via an initiating mechanism involving its metabolite, catechol estrogen (CE). To examine this hypothesis, we carried out a multigenic case-control study of 469 incident breast cancer patients and 740 healthy controls to define the role of important genes involved in the different metabolic steps that protect against the potentially harmful effects of CE metabolism. We studied the 3 genes involved in CE detoxification by conjugation reactions involving methylation (catechol-O-methyltransferase, COMT), sulfation (sulfotransferase 1A1, SULT1A1), or glucuronidation (UDP-glucuronosyltransferase 1A1, UGT1A1), one (manganese superoxide dismutase, MnSOD) involved in protection against reactive oxidative species-mediated oxidation during the conversion of CEsemiquinone (CE-SQ) to CE-quinone (CE-Q), and 2 of the glutathione S-transferase superfamily, GSTM1 and GSTT1, involved in CE-Q metabolism. Support for this hypothesis came from the observations that (i) there was a trend toward an increased risk of breast cancer in women harboring a greater number of putative high-risk genotypes of these genes (p < 0.05); (ii) this association was stronger and more significant in those women who were more susceptible to estrogen [no history of pregnancy or older (>26 years) at first full-term pregnancy (FFTP)]; and (iii) the risks associated with having one or more high-risk genotypes were not the same in women having experienced different menarche-to-FFTP intervals, being more significant in women having been exposed to estrogen for a longer period (>12 years) before FFTP. Furthermore, because CE-Q can attack DNA, leading to the formation of double-strand breaks (DSB), we examined whether the relationship between cancer risk and the genotypic polymorphism of CE-metabolizing genes was modified by the genotypes of DSB repair genes, and found that a joint effect of CE-metabolizing genes and one of the two DSB repair pathways, the homologous recombination pathway, was significantly associated with breast cancer development. Based on comprehensive CE metabolizing gene profiles, our study provides support to the hypotheses that breast cancer can be initiated by estrogen exposure and that increased estrogen exposure confers a higher risk of breast cancer by causing DSB to DNA.Key words: breast cancer; estrogen; catechol estrogen; polymorphism; molecular epidemiology An increased risk of breast cancer due to prolonged exposure to estrogen has been well documented by epidemiological observations showing that estrogen-related risk factors, including age at menarche, age at menopause, parity and age at first full-term pregnancy (FFTP), are significantly associated with breast cancer risk. 1,2 Why estrogen exposure should increase breast cancer risk is an intriguing question that has not been conclusively answered. One simple explanation is that the proliferative effect of estrogen on breast epithelium promotes the growth of tumor cells, leading to progression of breast cancer. [3...

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Section: Resultsmentioning

confidence: 99%

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Cheng

Chen

Huang

et al. 2004

Intl Journal of Cancer

102

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“…Although endocytosis is a major negative feedback loop for EGFR, certain downstream signaling pathways still can be driven from the internalized receptors in endosomes while on the route for recycling or degradation. Clathrin‐coated membrane microdomains have been proposed to be particularly important for the activation of AKT and MAPK upon EGFR activation (Kim et al ., 2002). Nevertheless, EGFR transferred from CCP at plasma membrane to endosomes terminates PI3K–AKT signaling, while prolonging MAPK signaling (Fehrenbacher et al ., 2009; Vieira et al ., 1996).…”

Section: Discussionmentioning

confidence: 99%

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

et al. 2017

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Targeting the MEK/ERK pathway has been viewed as a promising strategy for cancer therapy. However, MEK inhibition leads to the compensatory PI3K/AKT activation and thus contributes to the desensitization of cancer cells to MEK inhibitors. The underlying molecular mechanism of this event is not yet understood. In this study, our data showed that the induction of Akt activity by MEK inhibitors was specifically observed in HER2‐positive breast cancer cells. Silence of HER2, or overexpression of HER2 kinase‐dead mutant, prevents the induction of Akt activation in response to MEK inhibition, indicating HER2 as a critical regulator for this event. Furthermore, HER2 Thr701 was demonstrated as a direct phosphorylation target of ERK1/2. Inhibition of this specific phosphorylation prolonged the dimerization of HER2 with EGFR in a clathrin‐dependent manner, leading to the enhanced activation of HER2 and EGFR tyrosine kinase and their downstream Akt pathway. These results suggest that suppression of ERK‐mediated HER2 Thr701 phosphorylation contributes to MEK inhibitor‐induced Akt activation.

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“…This inverse pattern further suggests that NKX3.1 is a key driver of luminal cell differentiation, whereas loss of NKX3.1 would allow luminal cells to dedifferentiate into a state with higher proliferative capacity thus making them more vulnerable to the acquisition of additional oncogenic events perhaps augmented by concurrent defects in DNA repair. Clearly such additional events are essential for prostate carcinogenesis given that PIN in NKX3.1 knockout mice does not progresses to overt prostate cancer, unless further genetic changes are incurred 5– 8 .…”

Section: Discussionmentioning

confidence: 99%

“…Additional studies showed that serial passage of PIN-like lesions from Nkx3.1 mutant mice can undergo progressively severe histopathological alterations 5 . Finally, loss of Nkx3.1 can cooperate with loss of Pten and p27 in prostate cancer development in mice 7, 8 , while Nkx3.1 overexpression inhibits cell proliferation in Pten null epithelial grafts 9 . These data indicate that the diminished expression of NKX3.1 that is frequently observed in human prostate cancers 10 is involved in the initial stage of prostate carcinogenesis.…”

Section: Introductionmentioning

confidence: 94%

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

Yang

Chung²,

et al. 2014

F1000Res

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NKX3.1 is a homeobox transcription factor whose function as a prostate tumor suppressor remains insufficiently understood because neither the transcriptional program governed by NKX3.1, nor its interacting proteins have been fully revealed. Using affinity purification and mass spectrometry, we have established an extensive NKX3.1 interactome which contains the DNA repair proteins Ku70, Ku80, and PARP, thus providing a molecular underpinning to previous reports implicating NKX3.1 in DNA repair. Transcriptomic profiling of NKX3.1-negative prostate epithelial cells acutely expressing NKX3.1 revealed a rapid and complex response that is a near mirror image of the gene expression signature of human prostatic intraepithelial neoplasia (PIN). Pathway and network analyses suggested that NKX3.1 actuates a cellular reprogramming toward luminal cell differentiation characterized by suppression of pro-oncogenic c-MYC and interferon-STAT signaling and activation of tumor suppressor pathways. Consistently, ectopic expression of NKX3.1 conferred a growth arrest depending on TNFα and JNK signaling. We propose that the tumor suppressor function of NKX3.1 entails a transcriptional program that maintains the differentiation state of secretory luminal cells and that disruption of NKX3.1 contributes to prostate tumorigenesis by permitting luminal cell de-differentiation potentially augmented by defects in DNA repair.

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Cooperativity of Nkx3.1 and Pten loss of function in a mouse model of prostate carcinogenesis

Cited by 293 publications

References 31 publications

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

Breast cancer risk associated with genotype polymorphism of the catechol estrogen‐metabolizing genes: A multigenic study on cancer susceptibility

MEK inhibitors induce Akt activation and drug resistance by suppressing negative feedback ERK‐mediated HER2 phosphorylation at Thr701

Systems analysis of the prostate tumor suppressor NKX3.1 supports roles in DNA repair and luminal cell differentiation

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