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

Boulanger, Corinne A.; Wagner, Kay Uwe; Smith, Gilbert H.

doi:10.1038/sj.onc.1208185

Cited by 187 publications

(193 citation statements)

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“…49,51 Moreover, PI-MECs can self-renew and give rise to fully functional mammary glands in transplantation studies, which establishes them as true pregnancy-related mammary stem cells. [49][50][51][52] PI-MECs can be readily identified in situ using the transgenic Rosa LSL-LacZ ;WAP-Cre reporter mouse (LSLLacZ, lox-stop-lox b-galactosidase), as the whey acidic protein (WAP) promoter is specifically and only temporarily activated in late pregnancy to drive Cre expression. This removes the upstream Lox-Stop-Lox codon and permanently activates LacZ only in the surviving PI-MEC cells and their progeny.…”

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p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

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In embryogenesis, p63 is essential to develop mammary glands. In the adult mammary gland, p63 is highly expressed in the basal cell layer that comprises myoepithelial and interspersed stem/progenitor cells, and has limited expression in luminal epithelial cells. In adult skin, p63 has a crucial role in the maintenance of epithelial stem cells. However, it is unclear whether p63 also has an equivalent role as a stem/progenitor cell factor in adult mammary epithelium. We show that p63 is essential in vivo for the survival and maintenance of parity-identified mammary epithelial cells (PI-MECs), a pregnancy-induced heterogeneous population that survives post-lactational involution and contain multipotent progenitors that give rise to alveoli and ducts in subsequent pregnancies. p63 þ / À glands are normal in virgin, pregnant and lactating states. Importantly, however, during the apoptotic phase of post-lactational involution p63 þ / À glands show a threefold increase in epithelial cell death, concomitant with increased activation of the oncostatin M/Stat3 and p53 pro-apoptotic pathways, which are responsible for this phase. Thus, p63 is a physiologic antagonist of these pathways specifically in this regressive stage. After the restructuring phase when involution is complete, mammary glands of p63 þ / À mice again exhibit normal epithelial architecture by conventional histology. However, using Rosa LSL-LacZ ;WAP-Cre transgenics (LSL-LacZ, lox-stop-lox b-galactosidase), a genetic in vivo labeling system for PI-MECs, we find that p63 þ / À glands have a 30% reduction in the number of PI-MEC progenitors and their derivatives. Importantly, PI-MECs are also cellular targets of pregnancy-promoted ErbB2 tumorigenesis. Consistent with their PI-MEC pool reduction, one-time pregnant p63 þ / À ErbB2 mice are partially protected from breast tumorigenesis, exhibiting extended tumor-free and overall survival, and reduced tumor multiplicity compared with their p63 þ / þ ErbB2 littermates. Conversely, in virgin ErbB2 mice p63 heterozygosity provides no survival advantage. In sum, our data establish that p63 is an important survival factor for pregnancy-identified PI-MEC progenitors in breast tissue in vivo.

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confidence: 99%

“…This removes the upstream Lox-Stop-Lox codon and permanently activates LacZ only in the surviving PI-MEC cells and their progeny. 49,50,52 We used this system to test whether p63 heterozygosity affects PI-MECs and their survival after involution. Again, there was no difference during pregnancy and lactation (data not shown).…”

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p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

et al. 2014

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“…Using the Cre-lox technology, a mammary epithelial subtype, which is abundant in nonlactating and non-pregnant, parous mice, was recently described [13]. These parity-induced mammary epithelial cells (PI-MEC) then permanently reside at the terminal ends of ducts (i.e.…”

Section: The Origination Of Parity-induced Mammary Epithelial Cells Dmentioning

confidence: 99%

“…When the transplanted hosts were impregnated, the self-renewed PI-MEC at the tips of duct side branches proliferated during early pregnancy to form the new secretory acini. The transplantation procedure itself had no effect on the activation of the WAP-Cre and Rosa-LacZ transgenes because mammary fragments from nulliparous double transgenic donors never produced outgrowths with uniformly distributed X-Gal-positive cells [13].…”

Section: Pi-mec Are Self-renewing and Pluripotentmentioning

confidence: 99%

“…To establish an estimate of the self-renewing ability of PI-MECs, mammary fragments containing X-Gal positive cells were transferred through four transplant generations [13]. Each successful transplant resulted in a 400-fold increase of the implanted epithelial population, which represents roughly an 8 to 9 (8.65)-fold doubling of the implanted cells.…”

Section: Pi-mec Are Self-renewing and Pluripotentmentioning

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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Tumors caused by overexpression and forced activation of Stat5 in mammary epithelial cells of transgenic mice are parity‐dependent and developed in aged, postestropausal females

Eilon

Groner

Barash

2007

Intl Journal of Cancer

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In transgenic mice overexpressing Stat5 or a constitutively activated Stat5 variant (STAT5ca), we show for the first time that parity is required for the development of tumors in postestropausal females. Tumors were detected in glands of multiparous transgenic female mice after latency period of 14 months, but rarely in their age-matched virgin (AMV) counterparts. This period was not affected by distinguishable tumor pathologies and was not dependent upon transgenic Stat5 variant. To associate Stat5 deregulation, parity and the postestropausal tumor occurrence with mammary cancer formation, the activities of endogenous and transgenic Stat5 were measured in the glands of aged multiparous and AMV females. No differences in phosphorylated Stat5 (pStat5) levels were found between the 2 cohorts. However, promoter sequences comprising the Stat5 binding sites from the cyclin D1 or the bcl-x genes associate differentially with acetylated histone H4 in aged multiparous and AMV STAT5ca transgenic females. Individual epithelial cells varied greatly with respect to the presence of nuclear pStat5. A small subset of epithelial cells, in which pStat5 and cyclin D1 were co-expressed, was exclusively present in the multiparous glands. Changes in chromatin structure might persist past the reproductive life time of the multiparous mice and contribute to the transcription of the cyclin D1 gene by activated Stat5. This may cause the detectable expression of cyclin D1 and add to the process of tumorigenesis. ' 2007 Wiley-Liss, Inc.Key words: transgenic mice; mammary gland; breast; Stat5; cancer; parity Epidemiological studies have established a correlation between parity and the incidence of breast cancer in women.1-3 Parity has a protective effect, which depends on an early age of full-term pregnancy and is augmented by the total number of pregnancies. 4,5 In contrast, first pregnancy in women at their 30s is considered a life time risk factor. 2,6 A transient increase in risk for breast cancer after delivery has also been found and augmented in women at their 30s. 7,8 The diversity between the protective and inductive effects of parity on breast cancer was mainly associated with the be-directional double edged action of sex steroid hormones. Estrogen and progesterone could induce breast cancer by growth promoting effect on premalignant or preexisting malignant cells and protect from the disease by exerting persistent changes during a critical period of adolescence with long terms effects on cell proliferation and stem cells population.9-14 The detailed mechanisms regulating the action of sex steroid hormones remain elusive, but most likely involve signaling pathways that govern the balance between apoptosis, proliferation and differentiation. Recently, the mammary microenvironment was also associated with the transient increase in breast cancer risk. It was proposed that remodeling of the mammary gland during involution induces proinflammatory and wound-healing signals that are pro-oncogenic and contribute to cancer promotion and p...

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

Cited by 187 publications

References 17 publications

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

p63 is a prosurvival factor in the adult mammary gland during post-lactational involution, affecting PI-MECs and ErbB2 tumorigenesis

Stem Cells, Hormones, and Mammary Cancer

Tumors caused by overexpression and forced activation of Stat5 in mammary epithelial cells of transgenic mice are parity‐dependent and developed in aged, postestropausal females

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