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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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Related in: MedlinePlus

Postn expression in human breast cancers. Anti-Postn immunohistochemistry showing Postn expression in the stroma of human mammary glands bearing hyperplastic lesions (A). However, some mammary tumors were found to acquire Postn expression independently of receptor status. Representatives of Postn-negative (A-B) and positive (C-D) are shown. The expression data are summarized in Table 1.
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Fig1: Postn expression in human breast cancers. Anti-Postn immunohistochemistry showing Postn expression in the stroma of human mammary glands bearing hyperplastic lesions (A). However, some mammary tumors were found to acquire Postn expression independently of receptor status. Representatives of Postn-negative (A-B) and positive (C-D) are shown. The expression data are summarized in Table 1.

Mentions: Postn has been shown to play multiple roles in tumor progression through activation of pathways involved in invasion, cellular survival, angiogenesis, and metastasis [15,42]. Furthermore, Postn expression levels were found to be increased in a high proportion of breast cancers [19-21]. Supporting this, our analysis of human tissue microarray (Figure 1) revealed that about 46% (16/35) of human breast cancers acquire Postn expression irrespective of receptor status (Table 1).Figure 1


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)

Postn expression in human breast cancers. Anti-Postn immunohistochemistry showing Postn expression in the stroma of human mammary glands bearing hyperplastic lesions (A). However, some mammary tumors were found to acquire Postn expression independently of receptor status. Representatives of Postn-negative (A-B) and positive (C-D) are shown. The expression data are summarized in Table 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4355979&req=5

Fig1: Postn expression in human breast cancers. Anti-Postn immunohistochemistry showing Postn expression in the stroma of human mammary glands bearing hyperplastic lesions (A). However, some mammary tumors were found to acquire Postn expression independently of receptor status. Representatives of Postn-negative (A-B) and positive (C-D) are shown. The expression data are summarized in Table 1.
Mentions: Postn has been shown to play multiple roles in tumor progression through activation of pathways involved in invasion, cellular survival, angiogenesis, and metastasis [15,42]. Furthermore, Postn expression levels were found to be increased in a high proportion of breast cancers [19-21]. Supporting this, our analysis of human tissue microarray (Figure 1) revealed that about 46% (16/35) of human breast cancers acquire Postn expression irrespective of receptor status (Table 1).Figure 1

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