Abnormal mammary development in 129: STAT1-null mice is stroma-dependent

Jane Q. Chen, Hidetoshi Mori, Robert Cardiff, Josephine F. Trott, Russell C. Hovey, Neil Hubbard, Jesse A. Engelberg, Clifford G Tepper, Brandon J. Willis, Imran Khan, Resmi Ravindran, Szeman R. Chan, Robert D. Schreiber, Alexander D Borowsky

Research output: Contribution to journalArticle

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Abstract

Female 129:Stat1-null mice (129S6/SvEvTac-Stat1<sup>tm1Rds</sup> homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment.

Original languageEnglish (US)
Article numbere0129895
JournalPLoS One
Volume10
Issue number6
DOIs
StatePublished - Jun 15 2015

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mammary development
Human Mammary Glands
mammary glands
Breast
Tumors
Fats
mice
Conditioned Culture Medium
breasts
Prolactin
epithelium
Epithelium
Progesterone
Adipose Tissue
Cytokines
prolactin
Growth and Development
Microarrays
progesterone
Estrogen Receptors

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Abnormal mammary development in 129 : STAT1-null mice is stroma-dependent. / Chen, Jane Q.; Mori, Hidetoshi; Cardiff, Robert; Trott, Josephine F.; Hovey, Russell C.; Hubbard, Neil; Engelberg, Jesse A.; Tepper, Clifford G; Willis, Brandon J.; Khan, Imran; Ravindran, Resmi; Chan, Szeman R.; Schreiber, Robert D.; Borowsky, Alexander D.

In: PLoS One, Vol. 10, No. 6, e0129895, 15.06.2015.

Research output: Contribution to journalArticle

Chen, JQ, Mori, H, Cardiff, R, Trott, JF, Hovey, RC, Hubbard, N, Engelberg, JA, Tepper, CG, Willis, BJ, Khan, I, Ravindran, R, Chan, SR, Schreiber, RD & Borowsky, AD 2015, 'Abnormal mammary development in 129: STAT1-null mice is stroma-dependent', PLoS One, vol. 10, no. 6, e0129895. https://doi.org/10.1371/journal.pone.0129895
Chen, Jane Q. ; Mori, Hidetoshi ; Cardiff, Robert ; Trott, Josephine F. ; Hovey, Russell C. ; Hubbard, Neil ; Engelberg, Jesse A. ; Tepper, Clifford G ; Willis, Brandon J. ; Khan, Imran ; Ravindran, Resmi ; Chan, Szeman R. ; Schreiber, Robert D. ; Borowsky, Alexander D. / Abnormal mammary development in 129 : STAT1-null mice is stroma-dependent. In: PLoS One. 2015 ; Vol. 10, No. 6.
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abstract = "Female 129:Stat1-null mice (129S6/SvEvTac-Stat1tm1Rds homozygous) uniquely develop estrogen-receptor (ER)-positive mammary tumors. Herein we report that the mammary glands (MG) of these mice have altered growth and development with abnormal terminal end buds alongside defective branching morphogenesis and ductal elongation. We also find that the 129:Stat1-null mammary fat pad (MFP) fails to sustain the growth of 129S6/SvEv wild-type and Stat1-null epithelium. These abnormalities are partially reversed by elevated serum progesterone and prolactin whereas transplantation of wild-type bone marrow into 129:Stat1-null mice does not reverse the MG developmental defects. Medium conditioned by 129:Stat1-null epithelium-cleared MFP does not stimulate epithelial proliferation, whereas it is stimulated by medium conditioned by epithelium-cleared MFP from either wild-type or 129:Stat1-null females having elevated progesterone and prolactin. Microarrays and multiplexed cytokine assays reveal that the MG of 129:Stat1-null mice has lower levels of growth factors that have been implicated in normal MG growth and development. Transplanted 129:Stat1-null tumors and their isolated cells also grow slower in 129:Stat1-null MG compared to wild-type recipient MG. These studies demonstrate that growth of normal and neoplastic 129:Stat1-null epithelium is dependent on the hormonal milieu and on factors from the mammary stroma such as cytokines. While the individual or combined effects of these factors remains to be resolved, our data supports the role of STAT1 in maintaining a tumor-suppressive MG microenvironment.",
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