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From the Vanderbilt-Ingram Cancer Center* and the Departments of Cancer Biology, Pathology, and Preventive Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
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Abstract |
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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- transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF- compared to bigenic MMTV-DNIIR/MMTV-TGF- 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-ßs 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.
or the chemical carcinogen, 7,12-dimethylbenz[a]anthracene (DMBA).6
Similarly, recent studies have shown that WAP-TGF-ß1 transgenic mice are resistant to induction of mammary tumors by injection of the mouse mammary tumor virus7,8
in agreement with the previous studies with MMTV-TGF-ß1 mice.6 The effect of endogenous TGF-ß signaling on mammary gland development has been examined in transgenic mice by expression of a truncated, kinase-defective, dominant-negative type II TGF-ß receptor (DNIIR) regulated by the MMTV promoter/enhancer. The resultant phenotype includes increased lobuloalveolar development in virgin female mice.9,10 MMTV-DNIIR mice developed by one group did not develop mammary tumors spontaneously, but did demonstrate enhanced mammary tumorigenesis in response to administration of the chemical carcinogen, 7,12-dimethylbenz[a]anthracene. Enhancement by DNIIR expression of tumor formation in response to carcinogen administration has also been observed in the lung11 and skin.12
In the present study, we have extended studies with the previously reported MMTV-DNIIR mice10
to show that inhibition of TGF-ß signaling in mammary epithelial cells impairs full lactational differentiation and retards postlactational involution. Because impaired involution has been associated with enhanced mammary tumor formation in other transgenic mouse studies,13-15
tumor formation in the MMTV-DNIIR mice was examined. Multiparous MMTV-DNIIR female mice were found to spontaneously develop mammary carcinomas with a long median latency (>2 years). Co-expression of the MMTV-DNIIR and MMTV-TGF- transgenes resulted in mammary tumor formation similar to that observed in MMTV-TGF- mice except that DNIIR expression suppressed stromal invasion. The data support the hypotheses that signaling from endogenous TGF-ß not only plays an important role in normal mammary gland physiology but also can suppress the early stage of tumor formation and contribute to tumor invasion once carcinomas have developed.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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DNIIR transgene was detected by polymerase chain reaction analysis using primers for 526-bp ß-globin exon 3 sequence as described.10
TGF- transgene was detected by polymerase chain reaction analysis using primers for TGF- as described.13
Transgenic Mice
The MMTV-DNIIR transgenic animals were generated by microinjection of the DNIIR from pRHC102(17) into (C57BL/6xDBA)F2 fertilized eggs, then bred to (C57BL/6) as described.10
Female mice homozygous for DNIIR transgene were mated two to six times to produce litters. C57BL/6 female wild-type (WT) mice were also bred to produce two to six litters and both of the above (31 DNIIR) and (28 WT) mice were used in the study. Male MMTV TGF- were mated to female MMTV-DNIIR mice, to obtain bigenic MMTV TGF-/DNIIR transgenic mice. Seventeen MMTV-TGF- and 19 MMTV-TGF-/DNIIR multiparous transgenic mice were also used in the study. Mice were housed in 12-hour dark/light cycles and fed standard chow and water. All mice were carefully examined by palpation for tumors weekly for 2.5 years. Mammary tumors were removed 3 to 4 weeks after detection, other organs were also removed for detection of metastasis if desired. Tissues were fixed in 4% formaldehyde and sections were stained with hematoxylin and eosin (H&E) for histological diagnosis. Histological sections were analyzed and photographed using a Olympus BX41 Microscope (Melville, NY).
Extraction of RNA and Northern Blot Hybridization
Total RNA was isolated from tumors as described previously.10 Total RNA was resolved by electrophoresis and then transferred to nylon membrane (Hybond-N). The membranes were probed with 32P-labeled cDNA: 0.6-kb EcoRI-XhoI fragment from plasmid RHC102 for DNIIR, 540-bp HindIII-BamHI fragment of pT7BC-1 for ß-casein, 630-bp SacI-PstI fragment of mWAP+ for WAP, and 0.7-kb BamHI-PstI fragment from SP65IB15 for cyclophilin.
In Situ Hybridization
The DNIIR 0.6-kb EcoRI-XhoI fragment from pRH-102 was inserted into SP72 and SP73 vectors to make the riboprobes in anti-sense and sense orientation, respectively. The DNIIR riboprobes were generated by transcribing the linearized plasmids with T7 polymerase. Single-stranded RNA was labeled with 35S-labeled UTP (100 µCi; specific activity, 1400Ci/mmol; NEN, Boston, MA). In situ hybridization was performed for 18 hours at 55°C as described previously.10 Slides were exposed for 3.5 weeks, then developed and counterstained with 0.1% toluidine blue.
Histology and Immunostaining
For immunostaining and H&E staining, paraffin-embedded sections were used. Tumors and other tissues were fixed in 4% paraformaldehyde, dehydrated, and embedded in paraffin. Sections (5 µm) were stained with H&E using standard procedures.
Immunostaining of ß-casein was performed as previously described.10 Sections were dewaxed, rehydrated, and digested with 0.05% saponin for 30 minutes. Staining was performed using Vectastain ABC kit (Vector Laboratories, Hercules, CA), according to the manufacturer’s instructions. Immunofluorescence reactions were performed using 1:1000 dilution of Streptavidin-C3 Conjugate (catalog no. S6402; Sigma Chemical Co., St. Louis, MO) for 30 minutes, then 1:10,000 dilution of Yo-Pro for 15 minutes, then sections were mounted with AqvaPoly/Mount (catalog no. 18606; Polysciences, Inc., Warrington, PA).
Postlactational Involution
Homozygous MMTV-DNIIR female mice were bred to WT males. Pups were fed for 10 days and removed. The mothers were sacrificed at 4, 7, and 10 days after weaning. Paraffin sections of formaldehyde-fixed mammary glands were stained using the Apoptosis Kit (catalog no. S7100-6; Oncor, Gaithersburg, MD) to identify apoptotic cells on day 4 glands. Slides were counterstained with 0.5% methyl green.
Statistical Analysis
Analyses of study results focused on estimating the time to tumor development for each of the study groups and comparing the incidence rates of each type of the tumor among different study groups. Because each mouse may develop one or more than one tumor in the same or different types of the tumor, tests of hypotheses concerning the significant differences of the incidence rates for each type of the tumor among different groups were performed using the generalized estimating equation method16,17 to adjust the intracorrelation effect for the mouse that had multiple tumors. For lifetime data analyses, the study groups were compared for survival with Kaplan-Meier estimates and log-rank tests. All tests of significance were two-sided, and differences were considered statistically significant when the P value was <0.05. All data were expressed as means ± SD. SAS version 8.02 and S-Plus 6 were used for all analyses.
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Results |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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We have previously shown that expression of MMTV-DNIIR results in a precocious mammary development in virgin female mice.10
The phenotype was consistent only in mice having two transgene alleles (homozygous), and these mice were frequently unable to feed their pups. Thus, we examined the mammary phenotype of the homozygous MMTV-DNIIR mice during pregnancy. Five MMTV-DNIIR along with three nontransgenic mice were sacrificed at day 15 of their first pregnancy. The third thoracic mammary gland from each animal was removed for whole mount examination. Mammary glands from four of the five transgenic mice showed greater lobuloalveolar development than the control nontransgenic mice (Figure 1; A to D
). The one transgenic mouse not showing a difference from controls did not have DNIIR transgene expression as determined by Northern blot analysis of RNA isolated from inguinal glands (data not shown). Histological examination of the MMTV-DNIIR glands showed more prominent vacuoles in the alveoli indicating a greater degree of differentiation in comparison to controls (Figure 1, C and D)
. Immunostaining for ß-casein demonstrated positively staining material in the lumen of alveoli and ducts from the MMTV-DNIIR mammary glands, the control glands demonstrated only intracellular staining (Figure 1, E and F)
indicating more advanced lactational differentiation as a result of transgene expression.
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; A to D). ß-Casein immunostaining also indicated little progression from the 15-day pregnant state (Figure 2, E and F)
. Northern blot analysis of ß-casein mRNA from WT and DNIIR 15-day pregnant and 1-day lactating mammary glands showed variable expression in all groups with no significant differences among the groups (Figure 3)
. However, analysis of WAP mRNA expression demonstrated a fourfold greater expression in DNIIR versus WT glands during pregnancy (mean ± SD = 0.35 ± 0.17 for DNIIR and 0.08 ± 0.1 for WT, P = 0.0246) (Figure 3)
. In the DNIIR mammary glands, there was only a fourfold increase in WAP mRNA expression from 15-day pregnant to 1-day lactating while there was the expected 28-fold increase in the WT glands. The data indicate that interference with TGF-ß-signaling mammary epithelial cells causes accelerated development and differentiation during early to mid pregnancy, but results in impaired mammary gland development during the last stages of pregnancy producing a lactating gland with many functional alveoli.
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To determine the effects of DNIIR expression on postlactational involution of the mammary gland, female mice that were able to have and feed full litters for 8 to 10 days were examined at 4, 7, and 10 days after weaning. For the 4-day involution time point, glands from four transgenic and five WT mice were examined histologically using H&E-stained paraffin sections and by Apoptag staining to compare rates of apoptosis. All glands from transgenic mice showed a phenotype reflective of the changes noted in the 1-day lactating glands with many fewer alveoli (Figure 4, A and B)
. Staining for apoptotic nuclei showed the high rate of apoptosis expected at this stage of involution in glands from both nontransgenic and transgenic animals. To determine whether there was a consistent difference in the rate of apoptosis in the two groups, 600 to 1000 epithelial nuclei from four transgenic and four nontransgenic mice were counted and scored positive or negative for Apoptag staining. The mean ± SD for the nontransgenic mice was 12.25 ± 4.27 and 8.8 ± 1.11 for the transgenic mice. Using a two-tailed, unpaired Student’s t-test, a P value of 0.1692 was obtained indicating that the difference was not significant. However, an examination of mammary glands at 7 (Figure 4, E and F)
and 10 (Figure 4, G and H)
days after weaning demonstrated consistent retardation of involution in the transgenic animals.
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Previous studies demonstrated that another line of MMTV-DNIIR mice have increased mammary tumor formation only after administration of the chemical carcinogen, DMBA.11
To determine whether abrogation of TGF-ß signaling in mammary epithelial cells could result in spontaneous mammary tumor formation, DNIIR transgene was maximized by utilization of female mice homozygous for the transgene that had experienced two pregnancies. It is well known that hormonal stimulation during pregnancy drives high levels of MMTV transgene expression. Under these circumstances, we observed a high frequency of spontaneous mammary carcinoma development with a long latency. Fifteen of 32 (47%) MMTV-DNIIR female mice developed mammary tumors with a median latency of 27.5 months (Figure 5A
and Table 1
). A comparable number of WT multiparous female mice were followed for the same time interval and only one tumor was observed in one mouse, an intraductal papilloma. Thus, the difference in mammary tumor formation between the two populations was highly significant demonstrating that expression of the MMTV-DNIIR transgene alone can significantly accelerate the development of mammary carcinomas and supporting the hypothesis that signaling from endogenous TGF-ßs can be tumor suppressive (Figure 5A)
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. It is of interest that adenocarcinomas tended to develop in older mice paralleling the human condition; three of the four adenocarcinomas developed in mice that were >2 years of age at the time of first detection of the tumor. Figure 5, B and C
, shows the typical histological appearance of CIS/HG-MIN whereas Figure 5D
illustrates the appearance of a poorly differentiated adenocarcinoma, and Figure 5E
shows an area of stromal invasion.
Previous studies have indicated that TGF-ß signaling in carcinoma plays an important role in the invasive capability of the cells.19-21
Thus, we were interested in determining the expression status of the DNIIR transgene in areas of carcinoma invasion. This was determined by Northern blot analysis of RNA extracted from tumors and by in situ hybridization using a transgene-specific probe as previously described.10
We were able to extract sufficient tumor RNA for Northern blotting from 10 of the 15 animals. All of the seven CIS/HG-MIN samples examined showed transgene expression, whereas one (animal 14, Table 1
) of three RNA samples from invasive carcinomas was negative by Northern analysis. By in situ hybridization, tumors exhibiting the CIS/HG-MIN pattern consistently showed transgene expression similar to that observed in nontumor ductal epithelial cells (Figure 6
; A to D). However, poorly differentiated adenocarcinomas frequently showed no in situ hybridization evidence of transgene expression (Figure 6E)
, and all areas of tumor invasion showed no transgene expression (Figure 6F)
even when other areas of the same tumor had evidence of transgene expression. The data are consistent with TGF-ß signaling in carcinoma cells being involved in the processes of invasion.
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-Induced Mammary Tumors
We have previously demonstrated that overexpression of a constitutively active TGF-ß1 in mammary epithelial cells suppressed tumor induction by MMTV-TGF-.6
Thus, we were interested in determining the effect of abrogation of endogenous TGF-ß signaling on MMTV-TGF- tumor induction and crossed female homozygous MMTV-DNIIR female mice with male heterozygous MMTV-TGF- mice to obtain bigenic animals with one allele of each transgene. The development of mammary tumors in these bigenic animals were compared with that observed in mice expressing only the MMTV-TGF- transgene. Similar to earlier reports,6,13
MMTV-TGF- mice developed tumors with a median latency of 
9 months. However, we observed a higher frequency of tumor development (13 of 16 animals) with a higher percentage of animals having mammary tumors in more than one gland (11 of 13 mice with mammary tumors) (Table 2
, Figure 7A
). Of the tumor group, all had at least one invasive adenocarcinoma, and 20 of the 43 mammary tumors (47%) were invasive adenocarcinomas with the remainder being CIS/HG-MIN.
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and MMTV-DNIIR transgenes, mammary tumors formed with approximately the same median latency and frequency as in the MMTV-TGF- mice (Table 3
, Figure 7A
). However, the bigenic mice had a decreased incidence of invasive adenocarcinomas compared to tumors found in MMTV-TGF- mice. Seventeen of 19 bigenic mice developed a total of 32 mammary carcinomas, but only 5 of the 17 animals with mammary tumors and 6 of the 32 tumors demonstrated invasion. The difference in invasion between the MMTV-TGF- and bigenic mice was highly significant, P = <0.001. Figure 7B
illustrates a typical area of invasion in a carcinoma arising in an MMTV-TGF- mouse and Figure 7C
shows a carcinoma in situ arising in a bigenic animal. As with the carcinomas arising in MMTV-DNIIR mammary glands, the areas of invasion in tumors arising in bigenic animals showed absence of MMTV-DNIIR transgene expression as determined by in situ hybridization (data not shown).
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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The question arises as to whether the altered differentiation during pregnancy and lactation and the retarded postlactational involution is causally related to the enhanced mammary tumor formation. Previous studies suggest that this may be the case. During postlactational involution, TGF-ß3 has been shown to be induced by milk stasis and to initiate apoptosis in the mammary gland epithelium.25 Partial inhibition of TGF-ß3 signaling by the DNIIR transgene could explain the retardation of involution in the MMTV-DNIIR mammary glands. TGF-ß signaling has been implicated in the induction of senescence in mammary epithelial cells.4,5,7 Further, parity-induced increases in TGF-ß3 expression have been proposed as a mechanism for the protective effects of pregnancy for breast cancer development.26 Thus, it is possible that the impaired TGF-ß-induced senescence of mammary epithelial cells by the dominant-negative transgene leaves more cells in the proliferative pool enhancing the probability of further mutations leading to cancer.
The spontaneous development of mammary tumors in mice expressing the DNIIR transgene is a very important result because it indicates that endogenous TGF-ß signaling suppresses mammary tumor formation initiated by endogenous events. This is the first demonstration that abrogation of signaling from endogenous TGF-ßs can result in accelerated tumor formation. This observation in combination with our previous demonstration that constitutively active TGF-ß1 driven by the MMTV promoter/enhancer caused suppression of mammary tumorigenesis induced by TGF- or the chemical carcinogen, DMBA6
strongly support the hypothesis that TGF-ß signaling is tumor suppressive in the mammary gland. There is considerable evidence for TGF-ß signaling being tumor suppressive in other organs systems for both experimental animals and humans.27
The results of the present study are somewhat different from those reported by another group with a line of MMTV-DNIIR mice developed in their laboratory9 where mammary tumors did not develop spontaneously. There are several potential reasons for the disparity, including strain differences (FVB/N strain in the previous study versus C57BL/6.DBA/2 in the present study) and level of transgene expression.
Cross breeding MMTV-DNIIR animals with MMTV-TGF- mice to obtain mice expressing both transgenes resulted in mammary tumor formation with a much shorter latency and was similar to those expressing only the MMTV-TGF- transgene (<10 months median latency). The major difference in mammary tumors arising in MMTV-TGF- compared to bigenic MMTV-DNIIR/MMTV-TGF- was the marked suppression of tumor invasion by DNIIR transgene expression. These findings are consistent with evidence indicating that TGF-ß signaling can enhance progression of carcinomas after they have developed. We have known for many years that carcinoma cells frequently lose the growth inhibitory response to TGF-ß and increase production of one or more of the TGF-ß isoforms (TGF-ß1, -ß2, and -ß3).27,28
High levels of TGF-ß locally can have effects on host cells that favor tumor growth (suppression of immune surveillance, stimulation of connective tissue formation, and angiogenesis).29
Some carcinoma cells that have become refractory to growth inhibition by TGF-ß can still respond in an autocrine and paracrine manner to TGF-ß, converting to a spindle morphology with increased plasticity and motility, changes that favor invasion and metastasis.19
Distant metastases are not observed as frequently in the MMTV-TGF- mice13,30
as in the MMTV-c-neu model.21,31
This could be in part because of the cystic nature and large size of the mammary tumors in the MMTV-TGF- mice precluding sufficient follow-up time for development of metastases. One pulmonary metastasis from a mammary tumor was observed in the bigenic mice expressing both the MMTV-TGF- and MMTV-DNIIR transgenes (Table 3)
, and this tumor was observed to express the DNIIR transgene by in situ hybridization with a DNIIR transgene-specific probe (data not shown). On the surface, this seems contradictory to the data presented herein concerning suppression of invasion by DNIIR transgene expression. However, it is possible that microenvironmental factors can result in loss of MMTV-DNIIR transgene expression resulting in invasion and metastasis with re-establishment of transgene expression by the microenvironment of the metastatic site.
In summary, we have demonstrated that partial blockage of TGF-ß signaling in mammary epithelial cells in female mice causes precocious mammary gland development during puberty and early pregnancy, with impaired development during late pregnancy and lactation and retarded postlactational involution. This is a common feature of transgenic mice expressing an oncogene in mammary epithelium13,15,32-34 and may contribute to the accelerated development of mammary tumors. Indeed, we show that abrogation of signaling from endogenous TGF-ßs can result in accelerated spontaneous mammary tumor development. Although the effect of TGF-ß signaling in the mammary gland will likely be contextual depending on initiating events, these results indicate that signaling from endogenous TGF-ßs suppresses formation of mammary tumors initiated by endogenous events. Further, we provide additional in vivo data supporting the hypothesis that, after tumors have developed, TGF-ß signaling can enhance carcinoma cell invasion and metastasis. This provides a potentially important target for therapy.21
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Footnotes |
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Supported by grants from the National Cancer Institute (R01 CA85492 and P30 CA68485 to H. L. M.) and the Vanderbilt-Ingram Cancer Center (support grant CA68485).
Accepted for publication July 1, 2003.
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