Reducing mammary cancer risk through premature stem cell senescence

Boulanger, Corinne A.; Smith, Gilbert H.

doi:10.1038/sj.onc.1204312

Cited by 85 publications

(68 citation statements)

References 33 publications

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“…during ductal growth and expansion in the post-pubertal female or when the mammary epithelial implant is growing in the transplanted mammary fat pad). The negative effect of TGF-β1 on the expansive self-renewal of PI-MEC supports our earlier observation regarding protection from mouse mammary tumor virus (MMTV)-induced mammary tumorigenesis in WAP-TGF-β1 transgenic females [18]. This might suggest that the cellular targets for MMTV-mediated neoplastic transformation are PI-MEC because multiple pregnancies accelerate MMTV-induced oncogenesis [7].…”

Section: Wap-tgf-β1 Expression Aborts Self-renewal Of Pi-mec In Transsupporting

confidence: 87%

“…In a study using WAP-TGF-β1 transgenic mice, it was observed that mammary epithelial stem cells were prematurely aged due to ectopic expression of TGF-β1 under the regulation of the WAP gene promoter [18]. To assess whether TGF-β1 expression in PI-MEC abolishes their capacity to self-renew, mammary epithelia from WAP-TGF-β1/WAP-Cre/Rosa-LacZ triple transgenic mice were transplanted into wild type recipients.…”

Section: Wap-tgf-β1 Expression Aborts Self-renewal Of Pi-mec In Transmentioning

confidence: 99%

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Stem Cells, Hormones, and Mammary Cancer

Smith¹

2008

Hormonal Carcinogenesis V

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Pregnancy and breast cancerThe incidence of breast cancer is influenced by age, genetics, ethnicity, diet, socioeconomic status, and reproductive history. The latter is the strongest and most reliable risk factor besides age and genetic susceptibility [1]. Reproductive factors have been associated with risk for breast cancer since the 17 th century, when the disease was noted to be more prevalent among Catholic nuns. It is now a well-established fact that a full-term pregnancy early in life is associated with a long-term risk reduction for developing breast cancer. A woman who has her first child after the age of 35 has approximately twice the risk of developing breast cancer as a woman who has a child before age 20 (see current NCI Cancer Fact Sheet on Pregnancy and Breast Cancer Risk). Despite this long-term reduction in breast cancer risk in parous women, epidemiologists agreed at a recent NCI-sponsored workshop on "Early Reproductive Events and Breast Cancer" (http://nci.nih.gov/cancerinfo/ere) that each gestation increases temporarily the likelihood for developing breast cancer [2]. This transient increase in breast cancer risk lasts for a few years after a full-term pregnancy.Pregnancy has a very similar dual effect on the etiology of mammary cancer in animal models. Like humans, parous rats and mice have a greatly reduced susceptibility to chemically induced mammary tumorigenesis compared to their nulliparous siblings [3]. Humans who carry germ line mutations in tumor susceptibility genes do not benefit from the protective effects of pregnancy, but have a significantly greater risk of developing the disease following one or multiple gestation cycles [4]. There are, however, conflicting reports whether lactation influences the onset of breast cancer in women with BRCA1 mutations. The current view on breast cancer as a stem cell disease is founded on compelling evidence that many breast cancers may arise as clonal expansions from epithelial progenitors with an infinite lifespan [5]. It has been hypothesized that unique properties of mammary stem cells, such as self-renewal, make this population a prime target for transformation and tumorigenesis. Several experimental breast cancer models support this hypothesis. The most venerable is the mammary tumor virus [6] model in mice, where MMTV proviral insertions produce mutated mammary cells, which attain immortality (escape from growth senescence) and produce clones of mammary cells with increased propensity to develop mammary cancer. Serial transplantations of these preneoplastic lesions result in the formation of hyperplastic/dysplastic ductal trees, suggesting that multipotent cells are affected by MMTV transformation and that they pass on their neoplastic properties to their descendants [7]. Morphologically undifferentiated cells,

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Section: Wap-tgf-β1 Expression Aborts Self-renewal Of Pi-mec In Transsupporting

confidence: 87%

Section: Wap-tgf-β1 Expression Aborts Self-renewal Of Pi-mec In Transmentioning

confidence: 99%

Stem Cells, Hormones, and Mammary Cancer

Smith¹

2008

Hormonal Carcinogenesis V

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“…In this report, we demonstrate that these cells are pluripotent, that is, capable of giving rise to all mammary epithelial subtypes and that they have an extended capacity to self-renew over multiple transplant generations. We previously reported that TGF-b1 expressed from the WAP promoter reduces mammary cancer risk by promoting premature senescence in mammary stem cells (Kordon et al, 1995;Boulanger and Smith, 2001). Here, we show that expression of activated TGF-b1 within the parity-induced epithelial cells severely curtails their self-renewing activity as determined by transplantation, but not their capacity to proliferate and produce epithelial progeny of diverse fates among the mammary epithelium in multigestational females when left in situ.…”

Section: Introductionmentioning

confidence: 76%

“…Therefore, the paucity of alveolar development is the result of extensive apoptosis and not from suppression of epithelial cell proliferation. In addition to this phenotype, transplants of WAP-TGF-b1-positive mammary tissue show an early growth senescence, which in the case of mouse mammary tumor virus-infected females results in a significant reduction in mammary cancer risk (Boulanger and Smith, 2001). Therefore, it was of interest to us to determine what effect TGF-b1 expression might have on WAP-Cre induction of LacZpositive cells in mice bearing both WAP-driven transgenes and the LacZ reporter and on the subsequent behavior of PI-MEC both in situ and in transplants.…”

Section: Effects Of Tgf-b1 Expression In Wap-cre-activated Epithelialmentioning

confidence: 99%

Parity-induced mouse mammary epithelial cells are pluripotent, self-renewing and sensitive to TGF-β1 expression

Wagner²,

2004

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A parity-induced mammary population, marked by b-galactosidase expression conditionally activated through cre-lox recombinase originates in WAP-Cre/Rosa-lox-STOP-lox-LacZ (WAP-Cre/Rosa-LacZ) female mice during pregnancy, lactation and involution. During subsequent pregnancies, these parity-induced mammary epithelial cells (PI-MEC) proliferated to produce new secretory acini composed of secretory luminal cells and myoepithelium. In serial transplantation assays, PI-MEC were able to self-renew over several transplant generations and to contribute significantly to the resulting mammary outgrowths. In limiting dilution transplantation, they proliferated to produce both luminal and myoepithelial cells, comprised both lobule-limited and duct-limited epithelial outgrowths, and differentiated into all the cellular subtypes recognized in murine mammary epithelium. TGF-b1 expression from the whey acidic protein promoter (WAP) in triply transgenic females did not prevent the appearance of PI-MEC after pregnancy despite the absence of full lactation or their ability to proliferate and produce progeny with diverse cellular fates in situ upon subsequent pregnancies. However, in transplants from triple transgenic parous females, the WAP-TGF-b1-positive PI-MEC did not contribute to the newly recapitulated mammary outgrowths, suggesting that they were incapable of expansive cellular proliferation (self-renewal). This result is consistent with our earlier publication that WAP-TGFb1 expression in mammary epithelium induces premature stem cell senescence in mammary transplants and decreases mammary cancer risk in mouse mammary tumor virus (MMTV)-infected females even after multiple pregnancies.

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“…In large measure, these animals are highly cancer-prone 21 . By contrast, a genetic manipulation that causes premature senescence of mammary epithelial cells suppresses the development of breast cancer in young mice exposed to the mouse mammary tumor virus 22 .…”

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confidence: 99%