Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-β receptor exhibit impaired mammary development and enhanced mammary tumor formation

Agnieszka E. Gorska, Roy A. Jensen, Yu Shyr, Mary E. Aakre, Neil A. Bhowmick, Harold L. Moses

Research output: Contribution to journalArticle

99 Citations (Scopus)

Abstract

We have previously shown that expression of a dominant-negative type II transforming growth factor-β receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-α mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-α transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-α compared to bigenic MMTV-DNIIR/MMTV-TGF-α was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-βs not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.

Original languageEnglish
Pages (from-to)1539-1549
Number of pages11
JournalAmerican Journal of Pathology
Volume163
Issue number4
DOIs
Publication statusPublished - 2003 Oct 1

Fingerprint

Growth Factor Receptors
Transforming Growth Factors
Transgenic Mice
Breast
Breast Neoplasms
Transgenes
Human Mammary Glands
Genetic Hybridization
Carcinoma
Pregnancy
Neoplasms
Carcinoma in Situ
Lactation
Hyperplasia
In Situ Hybridization
Epithelium

All Science Journal Classification (ASJC) codes

  • Pathology and Forensic Medicine

Cite this

@article{e9c6e42489da432a880865de7944e70b,
title = "Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-β receptor exhibit impaired mammary development and enhanced mammary tumor formation",
abstract = "We have previously shown that expression of a dominant-negative type II transforming growth factor-β receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-α mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-α transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-α compared to bigenic MMTV-DNIIR/MMTV-TGF-α was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-βs not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.",
author = "Gorska, {Agnieszka E.} and Jensen, {Roy A.} and Yu Shyr and Aakre, {Mary E.} and Bhowmick, {Neil A.} and Moses, {Harold L.}",
year = "2003",
month = "10",
day = "1",
doi = "10.1016/S0002-9440(10)63510-9",
language = "English",
volume = "163",
pages = "1539--1549",
journal = "American Journal of Pathology",
issn = "0002-9440",
publisher = "Elsevier Inc.",
number = "4",

}

Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-β receptor exhibit impaired mammary development and enhanced mammary tumor formation. / Gorska, Agnieszka E.; Jensen, Roy A.; Shyr, Yu; Aakre, Mary E.; Bhowmick, Neil A.; Moses, Harold L.

In: American Journal of Pathology, Vol. 163, No. 4, 01.10.2003, p. 1539-1549.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Transgenic mice expressing a dominant-negative mutant type II transforming growth factor-β receptor exhibit impaired mammary development and enhanced mammary tumor formation

AU - Gorska, Agnieszka E.

AU - Jensen, Roy A.

AU - Shyr, Yu

AU - Aakre, Mary E.

AU - Bhowmick, Neil A.

AU - Moses, Harold L.

PY - 2003/10/1

Y1 - 2003/10/1

N2 - We have previously shown that expression of a dominant-negative type II transforming growth factor-β receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-α mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-α transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-α compared to bigenic MMTV-DNIIR/MMTV-TGF-α was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-βs not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.

AB - We have previously shown that expression of a dominant-negative type II transforming growth factor-β receptor (DNIIR) in mammary epithelium under control of the MMTV promoter/enhancer causes alveolar hyperplasia and differentiation in virgin mice. Here we show that MMTV-DNIIR female mice have accelerated mammary gland differentiation during early pregnancy with impaired development during late pregnancy and lactation followed by delayed postlactational involution. Mammary tumors, mostly carcinoma in situ, developed spontaneously in the MMTV-DNIIR mice with a long median latency (27.5 months). Crossbreeding to MMTV-transforming growth factor (TGF)-α mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency more similar to those expressing only the MMTV-TGF-α transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF-α compared to bigenic MMTV-DNIIR/MMTV-TGF-α was the marked suppression of tumor invasion by DNIIR transgene expression. Invading carcinoma cells in both MMTV-DNIIR and bigenic animals showed loss of DNIIR transgene expression as determined by in situ hybridization. The data indicate that signaling from endogenous TGF-βs not only plays an important role in normal mammary gland physiology but also can also suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.

UR - http://www.scopus.com/inward/record.url?scp=0141537150&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0141537150&partnerID=8YFLogxK

U2 - 10.1016/S0002-9440(10)63510-9

DO - 10.1016/S0002-9440(10)63510-9

M3 - Article

C2 - 14507660

AN - SCOPUS:0141537150

VL - 163

SP - 1539

EP - 1549

JO - American Journal of Pathology

JF - American Journal of Pathology

SN - 0002-9440

IS - 4

ER -