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c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

Cantrell MA, Ebelt ND, Pfefferle AD, Perou CM, Van Den Berg CL - Oncotarget (2015)

Bottom Line: Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments.In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition.JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular & Molecular Biology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA.

ABSTRACT
Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.

No MeSH data available.


Related in: MedlinePlus

Absence of jnk2 increases the luminal cell population and BRCA1 expression in p53ko tumorsA.p53ko tumors were measured until reaching 1.5 cm diameter (n = 22 p53ko;jnk2wt, n = 18 p53ko;jnk2ko, Log rank test); B-C.p53ko tumors were immunostained and Ki-67+ and CK8/18+ cells were quantified (n = 5); D-E. Expression of basal (red) and luminal (blue) markers was measured in p53ko tumors (n = 8, E) and p53ko cell lines F. Western blot of BRCA1 expression in p53ko cells; G.p53ko cells were transfected with Brca1 promoter (BRCA1PR) or promoterless control (PRless) luciferase plasmids and assayed for promoter activity; H. Correlation of Brca1 expression and EMT-related gene expression was assessed in human tumors (UNC308, n = 308, and COMBINED855, n = 855) and p53ko mouse tumors (n = 15, P.C. = Pearson Correlation). A nonparametric, two-tailed t-test was used to detect statistical differences between two groups. The Pearson's correlation was performed using data in H. *p < 0.05, **p < 0.001, ***p < 0.0001.
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Figure 4: Absence of jnk2 increases the luminal cell population and BRCA1 expression in p53ko tumorsA.p53ko tumors were measured until reaching 1.5 cm diameter (n = 22 p53ko;jnk2wt, n = 18 p53ko;jnk2ko, Log rank test); B-C.p53ko tumors were immunostained and Ki-67+ and CK8/18+ cells were quantified (n = 5); D-E. Expression of basal (red) and luminal (blue) markers was measured in p53ko tumors (n = 8, E) and p53ko cell lines F. Western blot of BRCA1 expression in p53ko cells; G.p53ko cells were transfected with Brca1 promoter (BRCA1PR) or promoterless control (PRless) luciferase plasmids and assayed for promoter activity; H. Correlation of Brca1 expression and EMT-related gene expression was assessed in human tumors (UNC308, n = 308, and COMBINED855, n = 855) and p53ko mouse tumors (n = 15, P.C. = Pearson Correlation). A nonparametric, two-tailed t-test was used to detect statistical differences between two groups. The Pearson's correlation was performed using data in H. *p < 0.05, **p < 0.001, ***p < 0.0001.

Mentions: We next performed mammary gland transplants of p53ko;jnk2wt and p53ko;jnk2ko tissue into wt mice to assess whether JNK2 controls tumor development or mammary cell lineage commitment independently of p53 [25]. Similar to reports comparing p53ko;jnk2wt and p53ko;jnk2ko systemic mutant mice [26], no difference in tumor latency was noted. However, p53ko;jnk2ko tumors grow significantly faster than p53ko;jnk2wt tumors after palpation (Fig 4A, p < 0.0001). p53ko;jnk2ko tumors also exhibit 2.9 times more Ki-67 positive cells compared to p53ko;jnk2wt (Fig 4B, p = 0.0159). The JNK2 anti-proliferative response seen with the p53ko model differs from that observed in the MT model expressing wildtype p53 [23]. These data indicate that JNK2 may influence tumor growth through various downstream targets including p53.


c-Jun N-terminal kinase 2 prevents luminal cell commitment in normal mammary glands and tumors by inhibiting p53/Notch1 and breast cancer gene 1 expression.

Cantrell MA, Ebelt ND, Pfefferle AD, Perou CM, Van Den Berg CL - Oncotarget (2015)

Absence of jnk2 increases the luminal cell population and BRCA1 expression in p53ko tumorsA.p53ko tumors were measured until reaching 1.5 cm diameter (n = 22 p53ko;jnk2wt, n = 18 p53ko;jnk2ko, Log rank test); B-C.p53ko tumors were immunostained and Ki-67+ and CK8/18+ cells were quantified (n = 5); D-E. Expression of basal (red) and luminal (blue) markers was measured in p53ko tumors (n = 8, E) and p53ko cell lines F. Western blot of BRCA1 expression in p53ko cells; G.p53ko cells were transfected with Brca1 promoter (BRCA1PR) or promoterless control (PRless) luciferase plasmids and assayed for promoter activity; H. Correlation of Brca1 expression and EMT-related gene expression was assessed in human tumors (UNC308, n = 308, and COMBINED855, n = 855) and p53ko mouse tumors (n = 15, P.C. = Pearson Correlation). A nonparametric, two-tailed t-test was used to detect statistical differences between two groups. The Pearson's correlation was performed using data in H. *p < 0.05, **p < 0.001, ***p < 0.0001.
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Figure 4: Absence of jnk2 increases the luminal cell population and BRCA1 expression in p53ko tumorsA.p53ko tumors were measured until reaching 1.5 cm diameter (n = 22 p53ko;jnk2wt, n = 18 p53ko;jnk2ko, Log rank test); B-C.p53ko tumors were immunostained and Ki-67+ and CK8/18+ cells were quantified (n = 5); D-E. Expression of basal (red) and luminal (blue) markers was measured in p53ko tumors (n = 8, E) and p53ko cell lines F. Western blot of BRCA1 expression in p53ko cells; G.p53ko cells were transfected with Brca1 promoter (BRCA1PR) or promoterless control (PRless) luciferase plasmids and assayed for promoter activity; H. Correlation of Brca1 expression and EMT-related gene expression was assessed in human tumors (UNC308, n = 308, and COMBINED855, n = 855) and p53ko mouse tumors (n = 15, P.C. = Pearson Correlation). A nonparametric, two-tailed t-test was used to detect statistical differences between two groups. The Pearson's correlation was performed using data in H. *p < 0.05, **p < 0.001, ***p < 0.0001.
Mentions: We next performed mammary gland transplants of p53ko;jnk2wt and p53ko;jnk2ko tissue into wt mice to assess whether JNK2 controls tumor development or mammary cell lineage commitment independently of p53 [25]. Similar to reports comparing p53ko;jnk2wt and p53ko;jnk2ko systemic mutant mice [26], no difference in tumor latency was noted. However, p53ko;jnk2ko tumors grow significantly faster than p53ko;jnk2wt tumors after palpation (Fig 4A, p < 0.0001). p53ko;jnk2ko tumors also exhibit 2.9 times more Ki-67 positive cells compared to p53ko;jnk2wt (Fig 4B, p = 0.0159). The JNK2 anti-proliferative response seen with the p53ko model differs from that observed in the MT model expressing wildtype p53 [23]. These data indicate that JNK2 may influence tumor growth through various downstream targets including p53.

Bottom Line: Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments.In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition.JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression.

View Article: PubMed Central - PubMed

Affiliation: Institute of Cellular & Molecular Biology, College of Pharmacy, University of Texas at Austin, Dell Pediatric Research Institute, Austin, TX 78723, USA.

ABSTRACT
Breast cancer is a heterogeneous disease with several subtypes carrying unique prognoses. Patients with differentiated luminal tumors experience better outcomes, while effective treatments are unavailable for poorly differentiated tumors, including the basal-like subtype. Mechanisms governing mammary tumor subtype generation could prove critical to developing better treatments. C-Jun N-terminal kinase 2 (JNK2) is important in mammary tumorigenesis and tumor progression. Using a variety of mouse models, human breast cancer cell lines and tumor expression data, studies herein support that JNK2 inhibits cell differentiation in normal and cancer-derived mammary cells. JNK2 prevents precocious pubertal mammary development and inhibits Notch-dependent expansion of luminal cell populations. Likewise, JNK2 suppresses luminal populations in a p53-competent Polyoma Middle T-antigen tumor model where jnk2 knockout causes p53-dependent upregulation of Notch1 transcription. In a p53 knockout model, JNK2 restricts luminal populations independently of Notch1, by suppressing Brca1 expression and promoting epithelial to mesenchymal transition. JNK2 also inhibits estrogen receptor (ER) expression and confers resistance to fulvestrant, an ER inhibitor, while stimulating tumor progression. These data suggest that therapies inhibiting JNK2 in breast cancer may promote tumor differentiation, improve endocrine therapy response, and inhibit metastasis.

No MeSH data available.


Related in: MedlinePlus