Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors

Qiang Shen, Ivan P. Uray, Yuxin Li, Yun Zhang, Jamal Hill, Xiao Chun Xu, Matthew R. Young, Edward Gunther, Susan G. Hilsenbeck, Nancy H. Colburn, Lewis A. Chodosh, Powel H. Brown

Research output: Contribution to journalArticle

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Abstract

The oncogene erbB2 is overexpressed in 20% to 30% human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTVerbB2 mice by more than 11 weeks. By 52 weeks of age, 100% (18 of 18) of the untreated animals had developed mammary tumors, whereas 56% (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.

Original languageEnglish (US)
Pages (from-to)45-55
Number of pages11
JournalCancer Prevention Research
Volume1
Issue number1
DOIs
StatePublished - Jun 1 2008

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Transcription Factor AP-1
Estrogen Receptors
Transcription Factors
Breast Neoplasms
Doxycycline
Breast
Human Mammary Glands
Carcinogenesis
Neoplasms
Transducers
Oncogenes
Transgenic Mice
Epithelial Cells

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Cite this

Shen, Qiang ; Uray, Ivan P. ; Li, Yuxin ; Zhang, Yun ; Hill, Jamal ; Xu, Xiao Chun ; Young, Matthew R. ; Gunther, Edward ; Hilsenbeck, Susan G. ; Colburn, Nancy H. ; Chodosh, Lewis A. ; Brown, Powel H. / Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors. In: Cancer Prevention Research. 2008 ; Vol. 1, No. 1. pp. 45-55.
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title = "Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors",
abstract = "The oncogene erbB2 is overexpressed in 20{\%} to 30{\%} human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTVerbB2 mice by more than 11 weeks. By 52 weeks of age, 100{\%} (18 of 18) of the untreated animals had developed mammary tumors, whereas 56{\%} (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.",
author = "Qiang Shen and Uray, {Ivan P.} and Yuxin Li and Yun Zhang and Jamal Hill and Xu, {Xiao Chun} and Young, {Matthew R.} and Edward Gunther and Hilsenbeck, {Susan G.} and Colburn, {Nancy H.} and Chodosh, {Lewis A.} and Brown, {Powel H.}",
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Shen, Q, Uray, IP, Li, Y, Zhang, Y, Hill, J, Xu, XC, Young, MR, Gunther, E, Hilsenbeck, SG, Colburn, NH, Chodosh, LA & Brown, PH 2008, 'Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors', Cancer Prevention Research, vol. 1, no. 1, pp. 45-55. https://doi.org/10.1158/1940-6207.CAPR-08-0034

Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors. / Shen, Qiang; Uray, Ivan P.; Li, Yuxin; Zhang, Yun; Hill, Jamal; Xu, Xiao Chun; Young, Matthew R.; Gunther, Edward; Hilsenbeck, Susan G.; Colburn, Nancy H.; Chodosh, Lewis A.; Brown, Powel H.

In: Cancer Prevention Research, Vol. 1, No. 1, 01.06.2008, p. 45-55.

Research output: Contribution to journalArticle

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T1 - Targeting the activator protein 1 transcription factor for the prevention of estrogen receptor-negative mammary tumors

AU - Shen, Qiang

AU - Uray, Ivan P.

AU - Li, Yuxin

AU - Zhang, Yun

AU - Hill, Jamal

AU - Xu, Xiao Chun

AU - Young, Matthew R.

AU - Gunther, Edward

AU - Hilsenbeck, Susan G.

AU - Colburn, Nancy H.

AU - Chodosh, Lewis A.

AU - Brown, Powel H.

PY - 2008/6/1

Y1 - 2008/6/1

N2 - The oncogene erbB2 is overexpressed in 20% to 30% human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTVerbB2 mice by more than 11 weeks. By 52 weeks of age, 100% (18 of 18) of the untreated animals had developed mammary tumors, whereas 56% (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.

AB - The oncogene erbB2 is overexpressed in 20% to 30% human breast cancers and is most commonly overexpressed in estrogen receptor (ER)-negative breast cancers. Transgenic mice expressing erbB2 develop ER-negative mammary tumors, mimicking human breast carcinogenesis. Previously, we have shown that activator protein 1 (AP-1) regulates proliferation of ER-negative breast cancer cells. We hypothesized that blockade of AP-1 in mouse mammary epithelial cells will suppress ER-negative tumorigenesis induced by erbB2. Trigenic erbB2 mice were generated by crossing a bigenic pUHD-Tam67/MMTV-rtTA mouse to a MMTV-erbB2 mouse. The resulting trigenic mice develop tumors and express a doxycycline-inducible c-Jun dominant negative mutant (Tam67) in the mammary glands. In vivo AP-1 blockade by Tam67 expression started delayed mammary tumor formation in MMTVerbB2 mice by more than 11 weeks. By 52 weeks of age, 100% (18 of 18) of the untreated animals had developed mammary tumors, whereas 56% (9 of 16) of the doxycycline-treated trigenic mice developed tumors. In addition, the tumors that arose in the AP-1-blocked erbB2 mice failed to express Tam67. Twenty-five percent of the doxycycline-treated MMTV-erbB2 mice survived more than 72 weeks of age without developing mammary tumors. Examination of normal-appearing mammary glands from these mice showed that AP-1 blockade by Tam67 also significantly prevents the development of premalignant lesions in these glands. The expression of erbB2 either in normal mammary tissue or in mammary tumors was not altered. Our results show that blocking the AP-1 signaling in mammary cells suppresses erbB2-induced transformation, and show that the AP-1 transcription factor is a critical transducer of erbB2. These results provide a scientific rationale to develop targeted drugs that inhibit AP-1 to prevent the development of ER-negative breast cancer.

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