Estrogen Receptor-beta Mediates the Protective Effects of Aromatase Induction in the MMTV-Her-2/neu x Aromatase Double Transgenic Mice

Hareesh B. Nair, Rao P. Perla, Nameer B Kirma, Naveen K. Krishnegowda, Manonmani Ganapathy, Rajib Rajhans, Sujit S. Nair, Pothana Saikumar, Ratna K Vadlamudi, Rajeshwar R Tekmal

Research output: Contribution to journalArticle

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Abstract

Breast cancers amplified for the tyrosine kinase receptor Her-2/neu constitute ~30% of advanced breast cancer cases, and are characterized by hormone independence and aggressive growth, implicating this pathway in breast oncogenesis. The induction of Her-2/neu leads to tumor development in 60% of transgenic mice. We have previously examined the effects of estrogen in the MMTVHer-2/neu background by generating the MMTV-Her-2/neu x aromatase double transgenic mouse strain. MMTV-Her-2/neu x aromatase mice developed fewer mammary tumors than the Her-2/neu parental strain. Our present data show the induction of several estrogen-related genes, including the tumor suppressors BRCA1 and p53, and a decrease in several angiogenic factors. The phosphorylated forms of MAPK p42/44 and AKT were lower in the MMTV-Her-2/neu x aromatase double transgenic mice compared to the MMTVHer-2/neu parental strain; conversely, phospho-p38 levels were higher in the double transgenic strain. The ERβ-selective antagonist THC reversed these changes. The regulation of these factors by ERβ was confirmed in clones of MCF7 breast cancer cells overexpressing Her-2/neu in combination with ERβ, suggesting that ERβ may play a direct role in regulating MAPK and AKT pathways. In summary, the data suggest that ERβ may play a major role in decreasing tumorigenesis and that it may affect breast cancer cell proliferation and survival by altering MAPK and AKT activation as well as modulation of tumor suppressor and angiogenesis factors. Treatment with selective ERβ agonist may provide therapeutic advantages for the treatment and prevention of breast cancer.

Original languageEnglish (US)
Pages (from-to)26-36
Number of pages11
JournalHormones and Cancer
Volume3
Issue number1-2
DOIs
StatePublished - Apr 2012

Fingerprint

Estrogen Receptor beta
Aromatase
Transgenic Mice
Breast Neoplasms
Angiogenesis Inducing Agents
Estrogens
Carcinogenesis
Dronabinol
Mitogen-Activated Protein Kinase 1
Receptor Protein-Tyrosine Kinases
Tumor Suppressor Genes
Neoplasms
Cell Survival
Breast
Clone Cells
Cell Proliferation
Hormones
Growth

Keywords

  • Aromatase
  • Breast cancer
  • Estrogen receptor beta
  • Her2/neu

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Endocrine and Autonomic Systems

Cite this

Estrogen Receptor-beta Mediates the Protective Effects of Aromatase Induction in the MMTV-Her-2/neu x Aromatase Double Transgenic Mice. / Nair, Hareesh B.; Perla, Rao P.; Kirma, Nameer B; Krishnegowda, Naveen K.; Ganapathy, Manonmani; Rajhans, Rajib; Nair, Sujit S.; Saikumar, Pothana; Vadlamudi, Ratna K; Tekmal, Rajeshwar R.

In: Hormones and Cancer, Vol. 3, No. 1-2, 04.2012, p. 26-36.

Research output: Contribution to journalArticle

Nair, Hareesh B. ; Perla, Rao P. ; Kirma, Nameer B ; Krishnegowda, Naveen K. ; Ganapathy, Manonmani ; Rajhans, Rajib ; Nair, Sujit S. ; Saikumar, Pothana ; Vadlamudi, Ratna K ; Tekmal, Rajeshwar R. / Estrogen Receptor-beta Mediates the Protective Effects of Aromatase Induction in the MMTV-Her-2/neu x Aromatase Double Transgenic Mice. In: Hormones and Cancer. 2012 ; Vol. 3, No. 1-2. pp. 26-36.
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abstract = "Breast cancers amplified for the tyrosine kinase receptor Her-2/neu constitute ~30{\%} of advanced breast cancer cases, and are characterized by hormone independence and aggressive growth, implicating this pathway in breast oncogenesis. The induction of Her-2/neu leads to tumor development in 60{\%} of transgenic mice. We have previously examined the effects of estrogen in the MMTVHer-2/neu background by generating the MMTV-Her-2/neu x aromatase double transgenic mouse strain. MMTV-Her-2/neu x aromatase mice developed fewer mammary tumors than the Her-2/neu parental strain. Our present data show the induction of several estrogen-related genes, including the tumor suppressors BRCA1 and p53, and a decrease in several angiogenic factors. The phosphorylated forms of MAPK p42/44 and AKT were lower in the MMTV-Her-2/neu x aromatase double transgenic mice compared to the MMTVHer-2/neu parental strain; conversely, phospho-p38 levels were higher in the double transgenic strain. The ERβ-selective antagonist THC reversed these changes. The regulation of these factors by ERβ was confirmed in clones of MCF7 breast cancer cells overexpressing Her-2/neu in combination with ERβ, suggesting that ERβ may play a direct role in regulating MAPK and AKT pathways. In summary, the data suggest that ERβ may play a major role in decreasing tumorigenesis and that it may affect breast cancer cell proliferation and survival by altering MAPK and AKT activation as well as modulation of tumor suppressor and angiogenesis factors. Treatment with selective ERβ agonist may provide therapeutic advantages for the treatment and prevention of breast cancer.",
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AU - Kirma, Nameer B

AU - Krishnegowda, Naveen K.

AU - Ganapathy, Manonmani

AU - Rajhans, Rajib

AU - Nair, Sujit S.

AU - Saikumar, Pothana

AU - Vadlamudi, Ratna K

AU - Tekmal, Rajeshwar R

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