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Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.

Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F, Zhong H, Vazquez A, Kang Y, Karantza V - Autophagy (2014)

Bottom Line: We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation.Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene.Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

View Article: PubMed Central - PubMed

Affiliation: a Rutgers Cancer Institute of New Jersey ; New Brunswick , NJ USA.

ABSTRACT
Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1(+/-);MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

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Monoallelic Becn1 loss accelerates WNT1-driven tumorigenesis and gives rise to mammary tumors with TNFRSF11A-NFKB1 pathway activation and basal-like characteristics. Basal-like characteristics and TNFRSF11A-NFKB1 signaling activation are detected in spontaneous mammary tumors that arise faster in Becn1+/−;MMTV-Wnt1 (right) compared with Becn1+/+;MMTV-Wnt1 mice (left). (A) Kaplan-Meier curves for mammary tumor-free survival in Becn1+/+;MMTV-Wnt1 (n = 25) and Becn1+/−;MMTV-Wnt1 (n = 20) mice demonstrates decreased mammary tumor-free survival in Becn1+/−;MMTV-Wnt1 mice. (B–E) Examination of mammary tumors and premalignant MGs from Becn1+/+;MMTV-Wnt1 (left) and Becn1+/−;MMTV-Wnt1 (right) mice. (B) Representative images of H&E staining (top panel), KRT6 (green) and nuclear PGR (red) cell staining (second panel), KRT8 (green) and KRT14 (red) cell staining (third panel), and nuclear ESR1 staining (bottom panel) on tumor sections. (C) Heat map representation of microarray analysis confirms basal-like tumor characteristics along with higher CTNNB1 expression in tumors from Becn1+/−;MMTV-Wnt1 mice. Statistical significance of upregulation of a given signature on a group of samples was determined using a Fischer exact test for enrichment of samples with significant (P < 0.05) signature expression in the group relative to samples outside the group. (D) Representative images of TNFSF11 (top panel) and RELA (bottom panel) expression in mammary tumors, and (E) TNFSF11 (top panel), TNFRSF11A (center panel), and RELA (bottom panel) expression in premalignant MGs from 6- to 10-wk-old cohoused Becn1+/+;MMTV-Wnt1 and Becn1+/−;MMTV-Wnt1 littermates. P < 0.01 determined by a Mantel-Cox test for Kaplan-Meier curves. Scale bar: (B) 200 μm for H&Es; (B, D, and E) 30 μm for all other panels.
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f0007: Monoallelic Becn1 loss accelerates WNT1-driven tumorigenesis and gives rise to mammary tumors with TNFRSF11A-NFKB1 pathway activation and basal-like characteristics. Basal-like characteristics and TNFRSF11A-NFKB1 signaling activation are detected in spontaneous mammary tumors that arise faster in Becn1+/−;MMTV-Wnt1 (right) compared with Becn1+/+;MMTV-Wnt1 mice (left). (A) Kaplan-Meier curves for mammary tumor-free survival in Becn1+/+;MMTV-Wnt1 (n = 25) and Becn1+/−;MMTV-Wnt1 (n = 20) mice demonstrates decreased mammary tumor-free survival in Becn1+/−;MMTV-Wnt1 mice. (B–E) Examination of mammary tumors and premalignant MGs from Becn1+/+;MMTV-Wnt1 (left) and Becn1+/−;MMTV-Wnt1 (right) mice. (B) Representative images of H&E staining (top panel), KRT6 (green) and nuclear PGR (red) cell staining (second panel), KRT8 (green) and KRT14 (red) cell staining (third panel), and nuclear ESR1 staining (bottom panel) on tumor sections. (C) Heat map representation of microarray analysis confirms basal-like tumor characteristics along with higher CTNNB1 expression in tumors from Becn1+/−;MMTV-Wnt1 mice. Statistical significance of upregulation of a given signature on a group of samples was determined using a Fischer exact test for enrichment of samples with significant (P < 0.05) signature expression in the group relative to samples outside the group. (D) Representative images of TNFSF11 (top panel) and RELA (bottom panel) expression in mammary tumors, and (E) TNFSF11 (top panel), TNFRSF11A (center panel), and RELA (bottom panel) expression in premalignant MGs from 6- to 10-wk-old cohoused Becn1+/+;MMTV-Wnt1 and Becn1+/−;MMTV-Wnt1 littermates. P < 0.01 determined by a Mantel-Cox test for Kaplan-Meier curves. Scale bar: (B) 200 μm for H&Es; (B, D, and E) 30 μm for all other panels.

Mentions: As shown (Fig. 7A; Fig. S5A), Becn1+/−;MMTV-Wnt1 mice displayed significantly shorter mammary tumor-free survival (4 vs. 7.2 mo; P 0.004) and overall survival (4.7 vs. 7.5 mo; P < 0.001) compared with Becn1+/+;MMTV-Wnt1 mice. Consistent with defective autophagy status, mammary tumors from Becn1+/−;MMTV-Wnt1 mice showed reduced LC3B levels and SQSTM1 aggregates (Fig. S5B). Tumors arising in Becn1+/+;MMTV-Wnt1 mice displayed known characteristics of MMTV-Wnt1 mammary tumors,40 as they were KRT6-positive adenosquamous carcinomas with high KRT8 and low KRT14 levels, and variable ESR (estrogen receptor) and PGR expression (Fig. 7B). Mammary tumors from Becn1+/−;MMTV-Wnt1 mice were also mostly adenosquamous carcinomas, but exhibited higher KRT6 levels, were more basal-like, as KRT14 expression was very prominent, and did not express ER or PGR (Fig. 7B). Furthermore, while proliferation was similar, apoptosis was suppressed in tumors from Becn1+/−;MMTV-Wnt1 mice (Fig. S5C and S5D).


Autophagy regulator BECN1 suppresses mammary tumorigenesis driven by WNT1 activation and following parity.

Cicchini M, Chakrabarti R, Kongara S, Price S, Nahar R, Lozy F, Zhong H, Vazquez A, Kang Y, Karantza V - Autophagy (2014)

Monoallelic Becn1 loss accelerates WNT1-driven tumorigenesis and gives rise to mammary tumors with TNFRSF11A-NFKB1 pathway activation and basal-like characteristics. Basal-like characteristics and TNFRSF11A-NFKB1 signaling activation are detected in spontaneous mammary tumors that arise faster in Becn1+/−;MMTV-Wnt1 (right) compared with Becn1+/+;MMTV-Wnt1 mice (left). (A) Kaplan-Meier curves for mammary tumor-free survival in Becn1+/+;MMTV-Wnt1 (n = 25) and Becn1+/−;MMTV-Wnt1 (n = 20) mice demonstrates decreased mammary tumor-free survival in Becn1+/−;MMTV-Wnt1 mice. (B–E) Examination of mammary tumors and premalignant MGs from Becn1+/+;MMTV-Wnt1 (left) and Becn1+/−;MMTV-Wnt1 (right) mice. (B) Representative images of H&E staining (top panel), KRT6 (green) and nuclear PGR (red) cell staining (second panel), KRT8 (green) and KRT14 (red) cell staining (third panel), and nuclear ESR1 staining (bottom panel) on tumor sections. (C) Heat map representation of microarray analysis confirms basal-like tumor characteristics along with higher CTNNB1 expression in tumors from Becn1+/−;MMTV-Wnt1 mice. Statistical significance of upregulation of a given signature on a group of samples was determined using a Fischer exact test for enrichment of samples with significant (P < 0.05) signature expression in the group relative to samples outside the group. (D) Representative images of TNFSF11 (top panel) and RELA (bottom panel) expression in mammary tumors, and (E) TNFSF11 (top panel), TNFRSF11A (center panel), and RELA (bottom panel) expression in premalignant MGs from 6- to 10-wk-old cohoused Becn1+/+;MMTV-Wnt1 and Becn1+/−;MMTV-Wnt1 littermates. P < 0.01 determined by a Mantel-Cox test for Kaplan-Meier curves. Scale bar: (B) 200 μm for H&Es; (B, D, and E) 30 μm for all other panels.
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f0007: Monoallelic Becn1 loss accelerates WNT1-driven tumorigenesis and gives rise to mammary tumors with TNFRSF11A-NFKB1 pathway activation and basal-like characteristics. Basal-like characteristics and TNFRSF11A-NFKB1 signaling activation are detected in spontaneous mammary tumors that arise faster in Becn1+/−;MMTV-Wnt1 (right) compared with Becn1+/+;MMTV-Wnt1 mice (left). (A) Kaplan-Meier curves for mammary tumor-free survival in Becn1+/+;MMTV-Wnt1 (n = 25) and Becn1+/−;MMTV-Wnt1 (n = 20) mice demonstrates decreased mammary tumor-free survival in Becn1+/−;MMTV-Wnt1 mice. (B–E) Examination of mammary tumors and premalignant MGs from Becn1+/+;MMTV-Wnt1 (left) and Becn1+/−;MMTV-Wnt1 (right) mice. (B) Representative images of H&E staining (top panel), KRT6 (green) and nuclear PGR (red) cell staining (second panel), KRT8 (green) and KRT14 (red) cell staining (third panel), and nuclear ESR1 staining (bottom panel) on tumor sections. (C) Heat map representation of microarray analysis confirms basal-like tumor characteristics along with higher CTNNB1 expression in tumors from Becn1+/−;MMTV-Wnt1 mice. Statistical significance of upregulation of a given signature on a group of samples was determined using a Fischer exact test for enrichment of samples with significant (P < 0.05) signature expression in the group relative to samples outside the group. (D) Representative images of TNFSF11 (top panel) and RELA (bottom panel) expression in mammary tumors, and (E) TNFSF11 (top panel), TNFRSF11A (center panel), and RELA (bottom panel) expression in premalignant MGs from 6- to 10-wk-old cohoused Becn1+/+;MMTV-Wnt1 and Becn1+/−;MMTV-Wnt1 littermates. P < 0.01 determined by a Mantel-Cox test for Kaplan-Meier curves. Scale bar: (B) 200 μm for H&Es; (B, D, and E) 30 μm for all other panels.
Mentions: As shown (Fig. 7A; Fig. S5A), Becn1+/−;MMTV-Wnt1 mice displayed significantly shorter mammary tumor-free survival (4 vs. 7.2 mo; P 0.004) and overall survival (4.7 vs. 7.5 mo; P < 0.001) compared with Becn1+/+;MMTV-Wnt1 mice. Consistent with defective autophagy status, mammary tumors from Becn1+/−;MMTV-Wnt1 mice showed reduced LC3B levels and SQSTM1 aggregates (Fig. S5B). Tumors arising in Becn1+/+;MMTV-Wnt1 mice displayed known characteristics of MMTV-Wnt1 mammary tumors,40 as they were KRT6-positive adenosquamous carcinomas with high KRT8 and low KRT14 levels, and variable ESR (estrogen receptor) and PGR expression (Fig. 7B). Mammary tumors from Becn1+/−;MMTV-Wnt1 mice were also mostly adenosquamous carcinomas, but exhibited higher KRT6 levels, were more basal-like, as KRT14 expression was very prominent, and did not express ER or PGR (Fig. 7B). Furthermore, while proliferation was similar, apoptosis was suppressed in tumors from Becn1+/−;MMTV-Wnt1 mice (Fig. S5C and S5D).

Bottom Line: We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation.Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene.Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

View Article: PubMed Central - PubMed

Affiliation: a Rutgers Cancer Institute of New Jersey ; New Brunswick , NJ USA.

ABSTRACT
Earlier studies reported allelic deletion of the essential autophagy regulator BECN1 in breast cancers implicating BECN1 loss, and likely defective autophagy, in tumorigenesis. Recent studies have questioned the tumor suppressive role of autophagy, as autophagy-related gene (Atg) defects generally suppress tumorigenesis in well-characterized mouse tumor models. We now report that, while it delays or does not alter mammary tumorigenesis driven by Palb2 loss or ERBB2 and PyMT overexpression, monoallelic Becn1 loss promotes mammary tumor development in 2 specific contexts, namely following parity and in association with wingless-type MMTV integration site family, member 1 (WNT1) activation. Our studies demonstrate that Becn1 heterozygosity, which results in immature mammary epithelial cell expansion and aberrant TNFRSF11A/TNR11/RANK (tumor necrosis factor receptor superfamily, member 11a, NFKB activator) signaling, promotes mammary tumorigenesis in multiparous FVB/N mice and in cooperation with the progenitor cell-transforming WNT1 oncogene. Similar to our Becn1(+/-);MMTV-Wnt1 mouse model, low BECN1 expression and an activated WNT pathway gene signature correlate with the triple-negative subtype, TNFRSF11A axis activation and poor prognosis in human breast cancers. Our results suggest that BECN1 may have nonautophagy-related roles in mammary development, provide insight in the seemingly paradoxical roles of BECN1 in tumorigenesis, and constitute the basis for further studies on the pathophysiology and treatment of clinically aggressive triple negative breast cancers (TNBCs).

Show MeSH
Related in: MedlinePlus