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Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity.

Sriram R, Lo V, Pryce B, Antonova L, Mears AJ, Daneshmand M, McKay B, Conway SJ, Muller WJ, Sabourin LA - Breast Cancer Res. (2015)

Bottom Line: Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy.This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. roshankumar2733@yahoo.com.

ABSTRACT

Introduction: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.

Methods: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis.

Results: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn- animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn- environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15).

Conclusions: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

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Loss of Postn does not affect tumor growth in MMTV-Neu mice. (A and B) Representative mammary gland whole mounts from 4 month old virgin females showing multiple tumor foci in both wildtype and Postn(-/-) mice. (C-F) H & E staining of representative tumors collected at end point from wildtype (C and E) and Postn- (D and F) mice. Both cystic (C and D) and solid tumors (E and F) were observed. (G) Kaplan-Meier survival analysis of tumor-bearing mice. Log rank testing showed no significant delay in tumor progression for Postn(-/-) mice when compared to heterozygotes or wildtype mice. All three genotypes reached end point with similar kinetics. (H-K) Paraffin-embedded sections were stained for ErbB2 (H and J) or Postn (I and K). Tumors arising in Postn- females retained Neu expression. In Neu-induced tumors, Postn expression was restricted to the stromal compartment and was never found in the tumor cells. (L) Western blot analysis of mammary tumors (T) and whole gland (G) lysates. Supporting the IHC data, Postn was found to be expressed at low levels in tumors containing a small amount of stromal fibroblasts.
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Fig2: Loss of Postn does not affect tumor growth in MMTV-Neu mice. (A and B) Representative mammary gland whole mounts from 4 month old virgin females showing multiple tumor foci in both wildtype and Postn(-/-) mice. (C-F) H & E staining of representative tumors collected at end point from wildtype (C and E) and Postn- (D and F) mice. Both cystic (C and D) and solid tumors (E and F) were observed. (G) Kaplan-Meier survival analysis of tumor-bearing mice. Log rank testing showed no significant delay in tumor progression for Postn(-/-) mice when compared to heterozygotes or wildtype mice. All three genotypes reached end point with similar kinetics. (H-K) Paraffin-embedded sections were stained for ErbB2 (H and J) or Postn (I and K). Tumors arising in Postn- females retained Neu expression. In Neu-induced tumors, Postn expression was restricted to the stromal compartment and was never found in the tumor cells. (L) Western blot analysis of mammary tumors (T) and whole gland (G) lysates. Supporting the IHC data, Postn was found to be expressed at low levels in tumors containing a small amount of stromal fibroblasts.

Mentions: Therefore, to investigate whether Postn expression is required for mammary tumorigenesis in an ErbB2-positive model, the in-frame Neu deletion transgene under the MMTV promoter (MMTV-NeuNDL2-5) [31] was introduced into mice lacking Postn. Postn wild-type, heterozygotes and NeuNDL virgin females were monitored for tumor development. In all Postn genotypes, hyperplastic lesions or palpable tumors could be detected as early as 16 weeks of age with no differences in the number of observed lesions (Figure 2A,B and Figure S2 in Additional file 3). Similarly, no differences were observed in tumor growth as all the Postn genotypes reached end point with similar kinetics (Figure 2G). Further analysis of NeuNDL-Postn+/+ and Postn−/− tumors revealed a mixture of intracystic or encapsulated intraductal papillary carcinomas (Figure 2C-F) that retained Neu expression (Figure 2H,J). In addition, no changes were observed in CD31-positive tumor blood vessels or in the Ki-67 proliferative index (Figure S3 in Additional file 4). These findings suggest that Postn ablation does not prevent or delay primary tumor initiation or growth. Similar findings have been reported in the MMTV-PyMT mouse model [22].Figure 2


Loss of periostin/OSF-2 in ErbB2/Neu-driven tumors results in androgen receptor-positive molecular apocrine-like tumors with reduced Notch1 activity.

Sriram R, Lo V, Pryce B, Antonova L, Mears AJ, Daneshmand M, McKay B, Conway SJ, Muller WJ, Sabourin LA - Breast Cancer Res. (2015)

Loss of Postn does not affect tumor growth in MMTV-Neu mice. (A and B) Representative mammary gland whole mounts from 4 month old virgin females showing multiple tumor foci in both wildtype and Postn(-/-) mice. (C-F) H & E staining of representative tumors collected at end point from wildtype (C and E) and Postn- (D and F) mice. Both cystic (C and D) and solid tumors (E and F) were observed. (G) Kaplan-Meier survival analysis of tumor-bearing mice. Log rank testing showed no significant delay in tumor progression for Postn(-/-) mice when compared to heterozygotes or wildtype mice. All three genotypes reached end point with similar kinetics. (H-K) Paraffin-embedded sections were stained for ErbB2 (H and J) or Postn (I and K). Tumors arising in Postn- females retained Neu expression. In Neu-induced tumors, Postn expression was restricted to the stromal compartment and was never found in the tumor cells. (L) Western blot analysis of mammary tumors (T) and whole gland (G) lysates. Supporting the IHC data, Postn was found to be expressed at low levels in tumors containing a small amount of stromal fibroblasts.
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Related In: Results  -  Collection

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Fig2: Loss of Postn does not affect tumor growth in MMTV-Neu mice. (A and B) Representative mammary gland whole mounts from 4 month old virgin females showing multiple tumor foci in both wildtype and Postn(-/-) mice. (C-F) H & E staining of representative tumors collected at end point from wildtype (C and E) and Postn- (D and F) mice. Both cystic (C and D) and solid tumors (E and F) were observed. (G) Kaplan-Meier survival analysis of tumor-bearing mice. Log rank testing showed no significant delay in tumor progression for Postn(-/-) mice when compared to heterozygotes or wildtype mice. All three genotypes reached end point with similar kinetics. (H-K) Paraffin-embedded sections were stained for ErbB2 (H and J) or Postn (I and K). Tumors arising in Postn- females retained Neu expression. In Neu-induced tumors, Postn expression was restricted to the stromal compartment and was never found in the tumor cells. (L) Western blot analysis of mammary tumors (T) and whole gland (G) lysates. Supporting the IHC data, Postn was found to be expressed at low levels in tumors containing a small amount of stromal fibroblasts.
Mentions: Therefore, to investigate whether Postn expression is required for mammary tumorigenesis in an ErbB2-positive model, the in-frame Neu deletion transgene under the MMTV promoter (MMTV-NeuNDL2-5) [31] was introduced into mice lacking Postn. Postn wild-type, heterozygotes and NeuNDL virgin females were monitored for tumor development. In all Postn genotypes, hyperplastic lesions or palpable tumors could be detected as early as 16 weeks of age with no differences in the number of observed lesions (Figure 2A,B and Figure S2 in Additional file 3). Similarly, no differences were observed in tumor growth as all the Postn genotypes reached end point with similar kinetics (Figure 2G). Further analysis of NeuNDL-Postn+/+ and Postn−/− tumors revealed a mixture of intracystic or encapsulated intraductal papillary carcinomas (Figure 2C-F) that retained Neu expression (Figure 2H,J). In addition, no changes were observed in CD31-positive tumor blood vessels or in the Ki-67 proliferative index (Figure S3 in Additional file 4). These findings suggest that Postn ablation does not prevent or delay primary tumor initiation or growth. Similar findings have been reported in the MMTV-PyMT mouse model [22].Figure 2

Bottom Line: Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy.This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, ON, K1H 8M5, Canada. roshankumar2733@yahoo.com.

ABSTRACT

Introduction: Periostin (Postn) is a secreted cell adhesion protein that activates signaling pathways to promote cancer cell survival, angiogenesis, invasion, and metastasis. Interestingly, Postn is frequently overexpressed in numerous human cancers, including breast, lung, colon, pancreatic, and ovarian cancer.

Methods: Using transgenic mice expressing the Neu oncogene in the mammary epithelium crossed into Postn-deficient animals, we have assessed the effect of Postn gene deletion on Neu-driven mammary tumorigenesis.

Results: Although Postn is exclusively expressed in the stromal fibroblasts of the mammary gland, Postn deletion does not affect mammary gland outgrowth during development or pregnancy. Furthermore, we find that loss of Postn in the mammary epithelium does not alter breast tumor initiation or growth in mouse mammary tumor virus (MMTV)-Neu expressing mice but results in an apocrine-like tumor phenotype. Surprisingly, we find that tumors derived from Postn- animals express low levels of Notch protein and Hey1 mRNA but increased expression of androgen receptor (AR) and AR target genes. We show that tumor cells derived from wild-type animals do not proliferate when transplanted in a Postn- environment but that this growth defect is rescued by the overexpression of active Notch or the AR target gene prolactin-induced protein (PIP/GCDFP-15).

Conclusions: Together our data suggest that loss of Postn in an ErbB2/Neu/HER2 overexpression model results in apocrine-like tumors that activate an AR-dependent pathway. This may have important implications for the treatment of breast cancers involving the therapeutic targeting of periostin or Notch signaling.

Show MeSH
Related in: MedlinePlus