Role of JNK in Mammary Gland Development and Breast Cancer

Cellurale, Cristina Arrigo; Girnius, Nomeda; Jiang, Feng; Cavanagh-Kyros, Julie; Lu, Shaolei; Garlick, David S.; Mercurio, Arthur M.; Davis, Roger J.

doi:10.1158/0008-5472.can-11-1628

Cited by 87 publications

(81 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Compound JNK deficiency in epithelial cells of the prostate (this study), breast (2), and liver (9) causes an increase in carcinogenesis. This observation suggests that JNK may act to reduce tumor development in these epithelial tissues.…”

Section: Jnk and Pten Cooperate To Regulate The Development Of Invasivementioning

confidence: 89%

mentioning

confidence: 99%

“…These transcription factors represent an important component of the immediate-early gene response to mitogens and inflammatory stimuli (2). AP1 transcription factors are also implicated in dysregulated growth and tumor development (2). Significantly, JNK deficiency suppresses AP1-dependent gene expression and causes defects in cell proliferation, senescence, and apoptosis (3)(4)(5).…”

mentioning

confidence: 99%

“…These observations demonstrate that JNK can promote cancer. However, loss of JNK signaling can also promote development of other tumors (2,9,(12)(13)(14)(15). These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1).…”

mentioning

confidence: 99%

See 3 more Smart Citations

JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

Hübner

Mulholland

Standen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

The c-Jun NH 2 -terminal kinase (JNK) signal transduction pathway is implicated in cancer, but the role of JNK in tumorigenesis is poorly understood. Here, we demonstrate that the JNK signaling pathway reduces the development of invasive adenocarcinoma in the phosphatase and tensin homolog (Pten) conditional deletion model of prostate cancer. Mice with JNK deficiency in the prostate epithelium (ΔJnk ΔPten mice) develop androgen-independent metastatic prostate cancer more rapidly than control (ΔPten) mice. Similarly, prevention of JNK activation in the prostate epithelium (ΔMkk4 ΔMkk7 ΔPten mice) causes rapid development of invasive adenocarcinoma. We found that JNK signaling defects cause an androgen-independent expansion of the immature progenitor cell population in the primary tumor. The JNK-deficient progenitor cells display increased proliferation and tumorigenic potential compared with progenitor cells from control prostate tumors. These data demonstrate that the JNK and PTEN signaling pathways can cooperate to regulate the progression of prostate neoplasia to invasive adenocarcinoma.T he c-Jun NH 2 -terminal kinase (JNK) signaling pathway can target members of the activating protein 1 (AP1) group of transcription factors, including ATF2, c-Jun, JunB, and JunD (1). These transcription factors represent an important component of the immediate-early gene response to mitogens and inflammatory stimuli (2). AP1 transcription factors are also implicated in dysregulated growth and tumor development (2). Significantly, JNK deficiency suppresses AP1-dependent gene expression and causes defects in cell proliferation, senescence, and apoptosis (3-5). JNK may, therefore, play a role in carcinogenesis.Studies using mouse models of cancer have confirmed that JNK can play a key role in cancer. Thus, JNK deficiency reduces the development of Bcr/Abl-induced lymphoma (6) and KRas-induced lung tumors (7). Moreover, carcinogen-induced hepatocellular carcinoma (8-10) and skin cancer (11) can be reduced by JNK deficiency. These observations demonstrate that JNK can promote cancer. However, loss of JNK signaling can also promote development of other tumors (2, 9, 12-15). These opposing roles of JNK in tumor development (promotion or repression) may represent differences in JNK function between tumor types (1). Alternatively, these differences may reflect separate functions of JNK in tumor cells and the tumor microenvironment (9).Mutational inactivation of the tumor suppressor phosphatase and tensin homolog (PTEN) frequently occurs in human prostate cancer (16)(17)(18). Mouse models of Pten deficiency in the prostate epithelium demonstrate that loss of PTEN expression is sufficient to cause activation of the AKT signaling pathway, prostatic intraepithelial neoplasia (PIN) lesions, and subsequent development of castration-resistant prostate cancer (19). Loss of PTEN function is, therefore, established to be a key step in the development of prostate cancer. Importantly, PTEN inactivation is associated with increased activity of the...

show abstract

Section: Jnk and Pten Cooperate To Regulate The Development Of Invasivementioning

confidence: 89%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

See 2 more Smart Citations

JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

Hübner

Mulholland

Standen

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, paradoxically, studies have demonstrated both a protumorigenic (16,41,42) and a tumor- (43,44) role for the JNK family, with duration of activation and context both implicated in defining the response (45). A major consideration in addressing these contrasting results is that reports of JNK acting as a tumor suppressor have studied the formation of primary tumors (46)(47)(48), where JNKmediated activation of apoptosis has an inhibitory role. In contrast, the in vivo screen described here represents an advanced tumor setting and our functional analyses confirm the complex interplay of prosurvival and proapoptotic signaling via JNK, which has important implications for the use of JNK inhibitors as potential therapeutics in cancer (12).…”

Section: Discussionmentioning

confidence: 99%

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Ashenden

Weverwijk

Murugaesu

et al. 2017

Molecular Cancer Therapeutics

View full text Add to dashboard Cite

Chemotherapy remains the mainstay of treatment for advanced breast cancer; however, resistance is an inevitable event for the majority of patients with metastatic disease. Moreover, there is little information available to guide stratification of firstline chemotherapy, crucial given the common development of multidrug resistance. Here, we describe an in vivo screen to interrogate the response to anthracycline-based chemotherapy in a syngeneic metastatic breast cancer model and identify JNK signaling as a key modulator of chemotherapy response. Combining in vitro and in vivo functional analyses, we demonstrate that JNK inhibition both promotes tumor cell cytostasis and blocks activation of the proapoptotic protein Bax, thereby antagonizing chemotherapy-mediated cytotoxicity. To investigate the clinical relevance of this dual role of JNK signaling, we developed a proliferation-independent JNK activity signature and demonstrate high JNK activity to be enriched in triple-negative and basal-like breast cancer subtypes. Consistent with the dual role of JNK signaling in vitro, high-level JNK pathway activation in triplenegative breast cancers is associated both with poor patient outcome in the absence of chemotherapy treatment and, in neoadjuvant clinical studies, is predictive of enhanced chemotherapy response. These data highlight the potential of monitoring JNK activity as early biomarker of response to chemotherapy and emphasize the importance of rational treatment regimes, particularly when combining cytostatic and chemotherapeutic agents.

show abstract

Disruption of Jmjd3/p16Ink4a Signaling Pathway Causes Bizarre Parosteal Osteochondromatous Proliferation (BPOP)-like Lesion in Mice

Zhang

Wang

et al. 2020

Journal of Bone and Mineral Research

View full text Add to dashboard Cite

Bizarre parosteal osteochondromatous proliferation (BPOP), or Nora's lesion, is a rare benign osteochondromatous lesion. At present, the molecular etiology of BPOP remains unclear. JMJD3(KDM6B) is an H3K27me3 demethylase and counteracts polycomb‐mediated transcription repression. Previously, Jmjd3 was shown to be critical for bone development and osteoarthritis. Here, we report that conditional deletion of Jmjd3 in chondrogenic cells unexpectedly resulted in BPOP‐like lesion in mice. Biochemical investigations revealed that Jmjd3 inhibited BPOP‐like lesion through p16Ink4a. Immunohistochemistry and RT‐qPCR assays indicated JMJD3 and p16INK4A level were significantly reduced in human BPOP lesion compared with normal subjects. This was further confirmed by Jmjd3/Ink4a double‐gene knockout mice experiments. Therefore, our results indicated the pathway of Jmjd3/p16Ink4a may be essential for the development of BPOP in human. © 2021 American Society for Bone and Mineral Research (ASBMR).

show abstract

Role of JNK in Mammary Gland Development and Breast Cancer

Cited by 87 publications

References 52 publications

JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

JNK and PTEN cooperatively control the development of invasive adenocarcinoma of the prostate

An In Vivo Functional Screen Identifies JNK Signaling As a Modulator of Chemotherapeutic Response in Breast Cancer

Disruption of Jmjd3/p16Ink4a Signaling Pathway Causes Bizarre Parosteal Osteochondromatous Proliferation (BPOP)-like Lesion in Mice

Contact Info

Product

Resources

About