Reduced Androgen Receptor Expression Accelerates the Onset of ERBB2 Induced Breast Tumors in Female Mice (original) (raw)
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Somatic Expression of PyMT or Activated ErbB2 Induces Estrogen-Independent Mammary Tumorigenesis 1 2
Neoplasia, 2010
Estrogen signaling is required for the proliferation of normal breast epithelial cells. However, prophylactic inhibition of estrogen signaling fails to prevent 56% of human breast cancer cases. The underlying mechanism is not well understood. Aberrant activation of growth factor signaling is known to provide alternative proliferation pathways in breast cells that are fully transformed, but it is not known whether activation of growth factor signaling can substitute for estrogen signaling in causing aberrant proliferation in the normal breast epithelium. Here, we report that in a retrovirus-based somatic mouse model (replication-competent ALV-LTR splice acceptor/tumor virus A) that closely mimics the evolution of sporadic human breast cancers, mammary epithelial cells harboring PyMT or activated ErbB2 evolve into tumors independent of estrogen or other ovarian functions in contrast to previous observations of estrogen-dependent cancer formation in germ line mouse models of ErbB2 activation. Importantly, ErbB2 activation in normal mammary cells causes estrogen-independent proliferation in both estrogen receptor (ER)-negative cells as well as in normally quiescent ER-positive cells. Therefore, aberrant activation of growth factor signaling contributes to estrogen-independent proliferation of both preneoplastic and cancerous mammary cells, and prophylactic therapy against both growth factor signaling and estrogen signaling may need to be considered in women with increased risk of breast cancer.
Oncogene, 2006
Epidemiological studies indicate that parity enhances HER2/ErbB2/Neu-induced breast tumorigenesis. Furthermore, recent studies using multiparous, ErbB2/Neu-overexpressing mouse mammary tumor virus (MMTV-Neu) mice have shown that parity induces a population of cells that are targeted for ErbB2/Neu-induced transformation. Although parity accelerates mammary tumorigenesis, the pattern of tumor development in multiparous MMTV-Neu mice remains stochastic, suggesting that additional events are required for ErbB2/Neu to cause mammary tumors. Whether such events are genetic in nature or reflective of the dynamic hormonal control of the gland that occurs with pregnancy remains unclear. We postulated that young age at pregnancy initiation or chronic trophic maintenance of mammary epithelial cells might provide a cellular environment that significantly increases susceptibility to ErbB2/Neu-induced tumorigenesis. MMTV-Neu mice that were maintained pregnant or lactating beginning at 3 weeks of age demonstrated accelerated tumorigenesis, but this process was still stochastic, indicating that early pregnancy does not provide the requisite events of tumorigenesis. However, bitransgenic mice that were generated by breeding MMTV-Neu mice with a luteinizing hormone-overexpressing mouse model of ovarian hyperstimulation developed multifocal mammary tumors in an accelerated, synchronous manner compared to virgin MMTV-Neu animals. This synchrony of tumor development in the bitransgenic mice suggests that trophic maintenance of the mammary gland provides the additional events required for tumor formation and maintains the population of cells that are targeted by ErbB2/Neu for transformation. Both the synchrony of tumor appearance and the ability to characterize a window of commitment by ovariectomy/palpation studies permitted microarray analysis to evaluate changes in gene expression over a defined timeline that spans the progression from normal to preneoplastic mammary tissue. These approaches led to identification of several candidate genes whose expression changes in the mammary gland with commitment to ErbB2/Neu-induced tumorigenesis, suggesting that they may either be regulated by ErbB2/Neu and/or contribute to tumor formation.
Carcinogenesis, 2006
AKT1/PKB is a serine/threonine protein kinase that regulates biological processes such as proliferation, apoptosis and growth in a variety of cell types. To assess the oncogenic capability of an activated form of AKT in vivo we have generated several transgenic mouse lines that overexpress in the mammary epithelium the murine Akt1 gene modified with a myristoylation signal, which renders active this protein by localizing it to the plasma membrane. We demonstrate that expression of myristoylated AKT in the mammary glands increases the susceptibility of these mice to the induction of mammary tumors of epithelial origin by the carcinogen 9,10-dimethyl-1,2 benzanthracene (DMBA). We have found that while carcinogen-treated wild-type mice show mostly mammary tumors of sarcomatous origin, AKT transgenic mice treated with DMBA developed mainly adenocarcinoma or adenosquamous tumors, all of them displaying activated AKT. We analyzed other possible molecular alterations cooperating with AKT and found that neither Ras nor b-catenin/Wnt pathways seemed altered nor p53 mutated. We have found that 100% of mammary DMBA-induced tumors and benign lesions in myrAKT mice are estrogen receptor (ERa)-positive and are more frequent than in wild-type littermates. These data show that AKT activation cooperates with deregulation of the estrogen receptor in the DMBA-induced mammary tumorigenesis model and recapitulate two characteristics of some human breast tumors. Thus, our model might provide a preclinical relevant model system to study the role of AKT and ERa in breast tumorigenesis and the response of mammary gland tumors to chemotherapeutics.
Somatic expression of PyMT or activated ErbB2 induces estrogen-independent mammary tumorigenesis
Neoplasia (New York, N.Y.), 2010
Estrogen signaling is required for the proliferation of normal breast epithelial cells. However, prophylactic inhibition of estrogen signaling fails to prevent 56% of human breast cancer cases. The underlying mechanism is not well understood. Aberrant activation of growth factor signaling is known to provide alternative proliferation pathways in breast cells that are fully transformed, but it is not known whether activation of growth factor signaling can substitute for estrogen signaling in causing aberrant proliferation in the normal breast epithelium. Here, we report that in a retrovirus-based somatic mouse model (replication-competent ALV-LTR splice acceptor/tumor virus A) that closely mimics the evolution of sporadic human breast cancers, mammary epithelial cells harboring PyMT or activated ErbB2 evolve into tumors independent of estrogen or other ovarian functions in contrast to previous observations of estrogen-dependent cancer formation in germ line mouse models of ErbB2 acti...
Mammary Gland Development and Tumorigenesis in Estrogen Receptor Knockout Mice
1997
Estrogens are important for the development of the mammary gland and strongly associated with oncogenesis in this tissue. The biological effects of estrogens are mediated through the estrogen receptor (ER),3 a member of the nuclear receptor superfamily. The estrogen/ER signaling pathway plays a central role in mammary gland development, regulating the expression and activity of other growth factors and their receptors. The generation of the ER knockout (ERKO) mouse has made it possible to directly understand the contribution of ER in mammary development and has provided an unique opportunity to study estrogen action in carcinogenesis. A mammary oncogene (Wnt-1) was introduced into the ERKO background to determine if the absence of the ER would affect the development of tumors induced by oncogenic stimulation. The development, hyperplasia, and tumorigenesis in mammary glands from the ERKO/Wnt-1 mouse line are described. These studies provide the impetus to evaluate the effect of other oncogenes in mammary tumorigenesis in the absence of estrogen/ER signaling.
Prolactin induces ERα-positive and ERα-negative mammary cancer in transgenic mice
Oncogene, 2003
The role of prolactin in human breast cancer has been controversial. However, it is now apparent that human mammary epithelial cells can synthesize prolactin endogenously, permitting autocrine/ paracrine actions within the mammary gland that are independent of pituitary prolactin. To model this local mammary production of prolactin (PRL), we have generated mice that overexpress prolactin within mammary epithelial cells under the control of a hormonally nonresponsive promoter, neurelated lipocalin (NRL). In each of the two examined NRL-PRL transgenic mouse lineages, female virgin mice display mammary developmental abnormalities, mammary intraepithelial neoplasias, and invasive neoplasms. Prolactin increases proliferation in morphologically normal alveoli and ducts, as well as in lesions. The tumors are of varied histotype, but papillary adenocarcinomas and adenosquamous neoplasms predominate. Neoplasms can be separated into two populations: one is estrogen receptor alpha (ERα) positive (greater than 15% of the cells stain for ERα), and the other is ERα−(<3%). ERα expression does not correlate with tumor histotype, or proliferative or apoptotic indices. These studies provide a mouse model of hormonally dependent breast cancer, and, perhaps most strikingly, a model in which some neoplasms retain ERα, as occurs in the human disease.
Breast Cancer Research Bcr, 2005
There is compelling evidence from transgenic mouse studies and analysis of mutations in human carcinomas indicating that the TGF-β signal transduction pathway is tumor suppressive. We have shown that overexpression of TGF-β1 in mammary epithelial cells suppresses the development of carcinomas and that expression of a dominant negative type II TGF-β receptor (DNIIR) in mammary epithelial cells under control of the MMTV promoter/enhancer increases the incidence of mammary carcinomas. Studies of human tumors have demonstrated inactivating mutations in human tumors of genes encoding proteins involved in TGF-β signal transduction, including DPC4/Smad4, Smad2, and the type II TGF-β receptor (TβRII). There is also evidence that TGF-β can enhance the progression of tumors. This hypothesis is being tested in genetically modified mice. To attain complete loss of TβRII, we have generated mice with loxP sites flanking exon 2 of Tgfbr2 and crossed them with mice expressing Cre recombinase under control of the MMTV promoter/enhancer to obtain Tgfbr2 mgKO mice. These mice show lobuloalveolar hyperplasia. Mice are being followed for mammary tumor development. Tgfbr2 mgKO mice that also express polyoma virus middle T antigen under control of the MMTV promoter (MMTV-PyVmT) develop mammary tumors with a significantly shorter latency than MMTV-PyVmT mice and show a marked increase in pulmonary metastases. Our data do not support the hypothesis that TGF-β signaling in mammary carcinoma cells is important for invasion and metastasis, at least in this model system. The importance of stromal-epithelial interactions in mammary gland development and tumorigenesis is well established. These interactions probably involve autocrine and paracrine action of multiple growth factors, including members of the TGF-β family, which are expressed in both stroma and epithelium. Again, to accomplish complete knockout of the type II TGF-β receptor gene in mammary stromal cells, FSP1-Cre and Tgfbr2 flox/flox mice were crossed to attain Tgfbr2 fspKO mice. The Despite over a decade of scrutiny and over 20 published reports from various countries, the degree to which ATM mutations lead to breast References 1. Gatti RA, Tward A, Concannon P: Cancer risk in ATM heterozygotes: a model of phenotypic and mechanistic differences between missense and truncating mutations. Mol Biol Metab 1999, 68:419-423. 2. Spring K, Ahangari F, Scott SP, Waring P, Purdie DM, Chen PC, Hourigan K, et al.: Mice heterozygous for mutation in Atm, the gene involved in ataxia-telangiectasia, have heightened susceptibility to cancer. Nat Genet 2002, 32:185-190. 3. Scott SP, Bendix R, Chen P, Clark R, Dork T, Lavin MF: Missense mutations but not allelic variants alter the function of ATM by dominant interference in patients with breast cancer. Proc Natl Acad Sci USA 2002, 99:925-930. 4. Concannon P: ATM heterozygosity and cancer risk. Nat Genet 2002, 32:89-90. 5. Chenevix-Trench G, Spurdle AB, Gatei M, Kelly H, Marsh A, Chen X, Donn K, et al.: Dominant negative ATM mutations in breast cancer families.