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[Cancer Research 63, 2747-2751, June 1, 2003]
© 2003 American Association for Cancer Research

Carcinogenesis

Identification of Novel Genetic Loci Contributing to 12-O-Tetradecanoylphorbol-13-acetate Skin Tumor Promotion Susceptibility in DBA/2 and C57BL/6 Mice1

Joe M. Angel2, Manuel Caballero and John DiGiovanni

The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957


   ABSTRACT
Top
 ABSTRACT
INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Genetic differences in susceptibility to two-stage skin carcinogenesis have been known for many years. Studies of genetic crosses of sensitive DBA/2 with resistant C57BL/6 mice suggested that multiple autosomal genes determine the sensitivity of these mice to 12-O-tetradecanoylphorbol-13-acetate (TPA) skin tumor promotion. Previous studies mapped one promotion susceptibility locus, Psl1, to distal chromosome 9. Analysis of TPA promotion susceptibility in (C57BL/6 x DBA/2)F1 x C57BL/6 mice and B x D recombinant inbred mouse strains suggested tentative associations of promotion susceptibility with several other chromosomal regions. To confirm these associations (C57BL/6 x BxD27)F2 mice analyzed for TPA promotion susceptibility were genotyped for polymorphic genetic markers mapping to chromosomal regions for which tentative associations had been previously detected. BxD27 mice are sensitive to TPA skin tumor promotion but carry the C57BL/6 allele of Psl1. Because Psl1 does not segregate in this cross, its effect on TPA promotion susceptibility is the same for all mice in the cross. The results of this analysis support the mapping of three novel promotion susceptibility loci to chromosomes 1, 2, and 19. Psl2 maps near D2Mit229 on distal chromosome 2, and inheritance of the dominant DBA/2 allele results in increased sensitivity to TPA. Psl3 maps near D1Mit511 on distal chromosome 1. Interestingly, inheritance of an allele from the resistant C57BL/6 parent results in increased sensitivity to TPA. Psl3 appears to have an additive affect, with heterozygous mice having a stronger response to TPA than mice homozygous for the DBA/2 allele and a weaker response to TPA than mice homozygous for the C57BL/6 allele. Psl4 maps near D19Mit38 on distal chromosome 19 and inheritance of the dominant C57BL/6 allele results in decreased TPA sensitivity. Analysis of the combined effects of these loci on TPA promotion susceptibility indicates that they contribute independently to the overall sensitivity to TPA.


   INTRODUCTION
Top
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
It is generally accepted that cancer is a multistage process during which the accumulation of numerous genetic lesions in an increasingly aberrant clonal subset of cells ultimately results in malignant transformation. In rare families, the germ-line transmission of a defective allele at a tumor suppresser locus, such as TP53, RB1, WT1, or APC (reviewed in Refs. 1 and 2 ), predisposes affected individuals to a greatly increased risk of developing certain forms of cancer. However, the majority of sporadic cancers cannot be explained by inheritance of a single defective yet highly penetrant tumor suppressor gene. Rather, epidemiological data suggest that cancer susceptibility in the general population is a function of multiple, poorly penetrant tumor susceptibility genes, each of which contributes to but is not solely responsible for predisposition to developing a particular type of cancer after exposure to certain environmental carcinogenic agents (reviewed in Ref. 3 ). It is clear that, unlike tumor suppressor genes, these genes act to alter the probability of cancer only in the presence of carcinogens. The observation that not every individual exposed to a carcinogen develops cancer demonstrates the importance of determining the role of tumor susceptibility genes in cancer risk. The notion that tumor susceptibility genes are encoded in the germ line is supported by the striking variation in tumor incidence among different inbred strains of mice or rats exposed to the same chemical. The fact that the relative sensitivity or resistance of a given rodent strain is a heritable trait supports the premise that specific genes regulate susceptibility to tumor development. The mapping of tumor susceptibility genes that contribute to interstrain variance in development of carcinogen-induced lung, liver, colon, mammary, kidney, hematopoietic, and skin tumors in segregating crosses of sensitive versus resistant mouse or rat strains has shown that genetic control of cancer susceptibility is complex, involving multiple genes (4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32) . Lee and Drinkwater (15) suggested that carcinogen sensitivity is determined by a combined effect of both sensitivity and resistance genes. In addition, Fijneman et al. (11) and van Wezel et al. (29) have shown that cancer susceptibility is further complicated by genic interactions. In one study, the effects of two colon tumor susceptibility loci (Scc4 and Scc5) have no obvious independent effects (29) . However, the two loci interact, with the effect of either locus being dependent on the genotype of the other locus.

Genetic differences in susceptibility to two-stage skin carcinogenesis have been known for many years (33, 34, 35, 36, 37, 38) . For example, SENCAR, LACA, CD-1, and DBA/2 mice are relatively susceptible to promotion by TPA,3 whereas BALB/c and C57BL/6 are relatively resistant (39, 40, 41, 42, 43) . The development of inbred mouse strains from the outbred SENCAR line that differ in susceptibility to TPA skin tumor promotion (44, 45, 46) supports the hypothesis that host genetic factors influence sensitivity to two-stage skin carcinogenesis. The major determinants of two-stage skin carcinogenesis susceptibility appear to be at the level of tumor promotion (reviewed in Refs. 3 and 35 ). Evidence supporting this includes (a) metabolism of skin carcinogens in the epidermis does not vary dramatically in different strains of mice, (b) the formation and removal of hydrocarbon DNA adducts is similar in the epidermis of various strains of mice, (c) mice initiated with direct-acting carcinogens or UV light in general show the same distribution in susceptibility to two-stage epidermal carcinogenesis, (d) mouse strains vary widely in their hyperplasiogenic response after topical exposure to phorbol ester skin tumor promoters, and (e) the recent identification of genetic loci that influence promotion susceptibility.

Analysis of genetic crosses of susceptible DBA/2 or C3H with resistant C57BL/6 mice indicated that susceptibility to TPA promotion is a multigenic autosomal trait that displays incomplete dominance (5 , 47, 48, 49, 50) . We previously reported the mapping of a TPA promotion susceptibility locus, Psl1, to mouse chromosome 9 in genetic crosses of C57BL/6 mice with DBA/2 mice (5 , 49) . This linkage was confirmed in (C57BL/6 x BxD22)F2 mice (50) . Analysis of TPA promotion susceptibility in (C57BL/6 x DBA/2)F1 x C57BL/6 backcross and/or BxD RI mice suggested other weak linkages that could not be confirmed in a panel of 96 (C57BL/6 x DBA/2)F2 intercross mice. To confirm the association of TPA promotion susceptibility with these chromosomal regions, we determined the susceptibility of 310 (C57BL/6 x BxD27)F2 female mice to TPA-promoted skin tumors and genotyped the mice for polymorphic markers mapping to each chromosomal region. These studies have confirmed linkages of novel TPA promotion susceptibility loci to chromosomes 1, 2, and 19.


   MATERIALS AND METHODS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Chemicals.
MNNG was purchased from Sigma Chemical Co. (St. Louis, MO). TPA was supplied by Chemicals for Cancer Research Inc. (Eden Prairie, MN). All other chemicals and reagents used were of the highest purity deemed necessary.

Mice.
C57BL/6J and BxD27 RI mice were purchased from The Jackson Laboratory (Bar Harbor, ME). C57BL/6 mice were crossed to BxD27 RI mice to generate (C57BL/6 x BxD27)F1 progeny. F1 mice were intercrossed to produce (C57BL/6 x BxD27)F2 mice. Mice were maintained in the Animal Resource Facility at The Science Park-Research Division as described previously (48) .

Tumor Experiments.
At 7–9 weeks of age, the backs of mice were carefully shaved with surgical clippers. Mice were allowed to rest for 2 days, and only those mice in the resting phase of the hair growth cycle were utilized. All chemicals were applied topically to the shaved area in 0.2 ml of acetone. Groups of mice were initiated with the direct-acting carcinogen MNNG (2.5 µmol/mouse). MNNG was used rather than the indirect-acting carcinogen 7,12-dimethylbenz(a)anthracene to avoid possible differences in tumor response due to metabolism of the initiator. Two weeks after initiation, mice received topical application of 13.6 nmol of TPA, given twice weekly. Incidence of skin papillomas was observed and recorded weekly, and promotion was conducted until a maximum response was obtained. Statistical analyses of differences between tumor multiplicity for each genotype were evaluated using the Mann-Whitney U test for groups with two variables and the Kruskal-Wallis rank-sum test for groups with more than two variables. Differences between tumor incidence of each group were evaluated by {chi}2 analysis.

Genotype Analysis.
Genotyping was carried out by PCR analysis of polymorphic microsatellite markers as described previously (5) , using microsatellite PCR primers purchased from Research Genetics (Huntsville, AL). PCR reactions were carried out using a MJ Research (Waltham, MA) thermocycler. The PCR products obtained were analyzed by electrophoresis through 3% agarose containing ethidium bromide and visualization of the bands under UV light.


   RESULTS
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Tentative Linkages to TPA Promotion Susceptibility Loci in (C57BL/6 x DBA/2)F1 x C57BL/6 and BxD RI Mice.
A genome-wide scan of 96 (C57BL/6 x DBA/2)F1 x C57BL/6 mice previously tested for sensitivity to TPA-promoted skin tumorigenesis suggested a linkage of a TPA promotion susceptibility locus with distal chromosome 9 (5 , 49) . This linkage was confirmed in (C57BL/6 x DBA/2)F2 mice and BxD RI strains (5 , 49) and, more recently, in (C57BL/6 x BxD22)F3 mice (50) . Weaker associations were also mapped to chromosomes 2, 4, and 10 (Table 1)Citation . These tentative linkages were not detected in (C57BL/6 x DBA/2)F2 mice or BxD RI mouse strains. In addition, sensitivity to TPA skin tumor promotion was determined for 22 BxD RI mouse strains (47) , and the resulting strain distribution pattern for TPA promotion susceptibility was compared with the strain distribution pattern of over 1600 genetic loci using Map Manager QTX. Tentative linkages were detected for several chromosomal regions (Table 2)Citation . These tentative linkages were not detected after analyses of (C57BL/6 x DBA/2)F1 x C57BL/6 or (C57BL/6 x DBA/2)F2 mice. None of these tentative linkages satisfied the criteria of Lander and Kruglyak (51) .


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  		Table 1 Tentative linkage of TPA promotion susceptibility in (C57BL/6 x DBA/2)F1 x C57BL/6 mice

 

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  		Table 2 Tentative linkage of TPA promotion susceptibility in BxD RI strains

 
Confirmation of Tentative Mapping of TPA Promotion Susceptibility Loci.
To confirm the mapping of additional TPA promotion susceptibility loci to the map locations identified in (C57BL/6 x DBA/2)F1 x C57BL/6 mice and BxD RI strains, the genotypes of 310 female (C57BL/6 x BxD27)F2 mice previously tested for TPA promotion susceptibility (50) were determined for polymorphic markers mapping to each chromosomal region (i.e., regions of chromosomes 1–4, 7, 8, 10, 13, 15, and 19). The BxD27 RI strain is sensitive to TPA skin tumor promotion but inherited the C57BL/6 allele of Psl1 on distal chromosome 9 (50) . As a result, Psl1 does not segregate in this intercross population. The BxD27 RI strain also inherited the central portion of chromosome 7 and the proximal portion of chromosome 14 from C57BL/6, therefore the tentative linkage of TPA promotion susceptibility loci to D7Rik78 and D14Rik50 could not be tested in this cross. Furthermore, a breakpoint occurred on chromosome 3 between lapls3–13 (31.5 cM) and D3Mit241 in BxD27. The region of chromosome 3 distal to D3Mit241 was inherited from C57BL/6, whereas the region of chromosome 3 proximal to lapls3–13 was inherited from DBA/2. Thus, only the region of chromosome 3 proximal to D3Mit241 could be tested in this cross. The association of TPA promotion susceptibility with genotype of the (C57BL/6 x BxD27)F2 mice was analyzed by the Kruskal-Wallis rank-sum test to compare tumor multiplicity for each genotype of each genetic marker (Table 3)Citation . Significant differences in tumor multiplicity were detected for markers mapping to chromosomes 1, 2, and 19 (Table 3)Citation , suggesting that TPA promotion susceptibility loci map to these chromosomal regions. Linkages were not detected for markers mapping to chromosomes 3, 4, 7, 8, 10, 13, or 15 (data not shown).


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  		Table 3 Association of TPA promotion susceptibility loci with mouse chromosomes 1, 2, and 19

 
The strongest association for a TPA promotion susceptibility locus was detected for distal chromosome 2 at D2Mit286 (Table 3)Citation . Inheritance of the DBA/2 allele resulted in increased tumor multiplicity (Table 3Citation ; Fig. 1Citation ). We have designated this locus as Psl2 (promotion susceptibility locus 2). These results are consistent with those observed in (C57BL/6 x DBA/2)F1 x C57BL/6 mice for D2Mit229 (Table 1)Citation and suggest that Psl2 is a susceptibility locus with the dominant allele being inherited from DBA/2.



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  		Fig. 1. Female (C57BL/6 x BxD27)F2 mice were initiated with MNNG and promoted with 13.6 nmol of TPA twice a week for 41 weeks. Tumors were counted once a week. Mice were genotyped for D1Mit511, D2Mit286, and D19Mit38 and scored as being homozygous C57BL/6 ({blacksquare}), homozygous DBA/2 ({blacktriangleup}), or heterozygous ({bullet}). Tumor multiplicity is the total number of tumors/number of mice at risk.

 
A TPA promotion susceptibility locus was also mapped to distal chromosome 1, with the most significant linkage mapping near D1Mit511 (Table 3)Citation . This locus appears to have an additive affect, with mice heterozygous for the locus having an intermediate response to TPA for tumor multiplicity (P = 0.03 when compared with homozygous C57BL/6; P = 0.04 when compared with homozygous DBA/2; Table 3Citation ; Fig. 1Citation ). Interestingly, the dominant susceptibility allele is inherited from the resistant C57BL/6 parent (Table 3Citation ; Fig. 1Citation ). These results are consistent with those observed in BxD RI mice for D1Mit145 (Table 2)Citation . We have designated this locus as Psl3 (promotion susceptibility locus 3).

A dominant C57BL/6 resistance locus was mapped to chromosome 19 (Table 3)Citation . Inheritance of the C57BL/6 allele of D19Mit38 resulted in a significant decrease in tumor multiplicity compared with mice homozygous for the DBA/2 allele (Table 3Citation ; Fig. 1Citation ). The decreased response of mice inheriting a C57BL/6 allele of D19Mit38 is consistent with the tumor response observed in BxD RI mice (Table 2)Citation . We have designated the chromosome 19 locus as Psl4 (promotion susceptibility locus 4).

Additive Effects of TPA Promotion Susceptibility Loci.
Lee and Drinkwater (15) suggested that the response of an individual to carcinogen exposure is determined by the additive effects of both modifier genes that increase or decrease response to the carcinogen. To determine whether the effects of Psl2, Psl3, and Psl4 on TPA skin tumor promotion are additive, the tumor response for mice inheriting each combination of genotypes for these loci was compared (Table 4)Citation . Analysis of tumor multiplicity by the Mann-Whitney rank-sum test indicated that genotypes could be divided into four statistically significant groups (Table 4)Citation . As expected, those mice inheriting the dominant susceptibility alleles of Psl2 and Psl3 and homozygous for the recessive allele of Psl4 (group A, Table 4Citation ) had the highest response to TPA. These mice would have the genotype A-B-cc, where A represents Psl2 (A is the DBA/2 allele, a is the C57BL/6 allele, - is either allele), B represents Psl3 (B is the C57BL/6 allele, b is the DBA/2 allele, - is either allele), and C represents Psl4 (C is the C57BL/6 allele, c is the DBA/2 allele, - is either allele). Mice inheriting the dominant susceptibility alleles of Psl2 and Psl3 and the dominant resistant allele of Psl4 (A-B-C-) have a reduced susceptibility to TPA (group B, Table 4Citation ), similar to that observed for mice in group B that inherited the susceptibility allele of either Psl2 or Psl3 and are homozygous for the recessive allele of Psl4 (A-bbcc and aaB-cc). Group B mice had a tumor incidence of 83.4% and a tumor multiplicity of 1.83 ± 0.11. Tumor multiplicity was significantly lower (P = 0.02) for mice in group B compared with mice in group A, although there was no significant difference in tumor incidence between the two groups. Group C (Table 4)Citation includes mice that inherited the dominant susceptibility allele of either Psl2 or Psl3 and the dominant resistance allele of Psl4 (A-bbC- or aaB-C-) and had a tumor incidence of 66.7% and a tumor multiplicity of 1.44 ± 0.17. Both tumor multiplicity (P = 0.004) and tumor incidence (P = 0.002) were significantly lower for mice in group C compared with mice in group B. The lowest responding group (group D, Table 4Citation ) includes mice that are homozygous for the recessive allele of Psl2 and Psl3 (aabbcc and aabbC-) and had a tumor incidence of 28.6% with a tumor multiplicity of 0.64 ± 0.30. Both tumor multiplicity (P = 0.04) and tumor incidence (P = 0.006) were significantly lower for mice in group D compared with mice in group C. Tumor susceptibility in this group appears to decrease with the inheritance of the dominant resistance allele of Psl4 (aabbC-) compared with those mice homozygous for the recessive allele of Psl4 (aabbcc); however, there was no significant difference in tumor incidence or tumor multiplicity between these two groups of mice. This may be due to the low numbers of mice in these two groups. These analyses indicate that each TPA promotion susceptibility locus contributes to the individual response to TPA, with TPA sensitivity increasing with an increasing inheritance of susceptibility loci and decreasing inheritance of resistance loci.


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  		Table 4 Additive effects of TPA promotion susceptibility loci

 

   DISCUSSION
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Susceptibility to TPA skin tumor promotion is a multigenic trait. We previously mapped a TPA promotion susceptibility locus, Psl1, to distal chromosome 9 (5 , 49) and tentatively mapped other loci to several unlinked chromosomal regions using (C57BL/6 x DBA/2)F1 x C57BL/6 and BxD RI mice. We took advantage of the observation that the sensitive BxD27 RI strain is homozygous for the C57BL/6 allele of Psl1 (50) and generated a mapping panel of 310 (C57BL/6 x BxD27)F2 mice in which Psl1 does not segregate to confirm the mapping of additional TPA promotion susceptibility loci.

The mapping of three novel TPA promotion susceptibility loci were confirmed in this study. Psl2 maps to a region of chromosome 2 near D2Mit286 at 73 cM from the centromere. Inheritance of the DBA/2 allele of Psl2 results in increased sensitivity to TPA skin tumor promotion. Psl3 maps to the distal end of chromosome 1 near D1Mit511 at 110 cM from the centromere. Inheritance of the C57BL/6 allele results in increased sensitivity to TPA skin tumor promotion. A third locus, Psl4, maps to chromosome 19 near D19Mit38 at 47 cM from the centromere. Inheritance of the C57BL/6 allele of this locus results in a decrease in TPA promotion susceptibility. Whereas the significance levels observed for Psl3 and Psl4 fail to meet the stringent requirements of Lander and Kruglyak (51) , it should be noted that this study was designed to test the hypothesis that TPA promotion susceptibility loci mapped to a limited number of chromosomal regions rather than to conduct a genome-wide scan. Thus, less stringent criteria of single-point significance levels of <0.05 are sufficient for assessing linkage.

Analysis of the effects of D1Mit511, D2Mit286, and D19Mit38 on TPA sensitivity in BxD RI strains supports the mapping of TPA promotion susceptibility loci to these chromosomal regions (data not shown). As shown in Table 2Citation , Map Manager QTX detected associations of TPA promotion susceptibility with D1Mit145, which maps approximately 20 cM proximal to D1Mit511, and with Rbp4, which maps about 9 cM proximal to D19Mit38. No linkage was detected in the BxD RI strains for markers mapping to chromosome 2. However, composite interval mapping, controlling for D1Mit145, revealed a peak association of TPA promotion susceptibility with D1Mit541 (P = 0.0006), which maps near D1Mit511 (Table 3)Citation , and a significant association (P = 0.003) for D1Mit511. Composite interval mapping, controlling for D1Mit145, also identified significant associations of TPA promotion susceptibility with D2Mit286 (P = 0.002) and D19Mit38 (P = 0.0006). Interestingly, D1Mit145 had no effect on tumor multiplicity in the (C57BL/6 x BxD27)F2 cross (data not shown).

As shown in Table 1Citation , an association of TPA promotion susceptibility with markers mapping near D2Mit286 was detected in the original (C57BL/6 x DBA/2)F1 x C57BL/6 mapping panel. However, associations were not detected for markers mapping near D1Mit511 or D19Mit38. The failure to detect linkages of TPA promotion susceptibility loci to these chromosomal regions in the (C57BL/6 x DBA/2)F1 x C57BL/6 mapping panel is likely due to the small size of the panel (96 mice) or to genic interactions.

Although other groups have mapped TPA promotion susceptibility loci in other genetic crosses, these three loci represent novel TPA promotion susceptibility loci not reported previously. Mock et al. (20) reported the mapping of a TPA promotion susceptibility locus to chromosome 5 and tentative linkages to chromosomes 9, 11, and 12. Nagase et al. (24 , 25) have also mapped several loci that influence skin tumor multiplicity in TPA promoted mice, including Skts8, which maps to distal chromosome 1. Although we cannot rule out the possibility that Skts8 and Psl3 are allelic, the observation that inheritance of the dominant allele of Skts8 results in decreased TPA sensitivity, whereas inheritance of the dominant allele of Psl3 results in increased TPA sensitivity, suggests that these are different genes.

We previously proposed that TPA promotion susceptibility in genetic crosses of C57BL/6 with DBA/2 mice is a multigenic trait involving at least three genes (47) . The model suggested that at least one gene increased susceptibility when inherited from C57BL/6. We have now identified three loci (Psl1, Psl2, and Psl3) that increase susceptibility to TPA skin tumor promotion. Inheritance of the dominant DBA/2 allele of Psl1 or Psl2 results in increased sensitivity to TPA skin tumor promotion. Inheritance of the dominant allele of Psl3 from the resistant C57BL/6 parent also results in increased sensitivity to TPA skin tumor promotion, as predicted in our genetic model. In addition, we have identified one locus, Psl4, that acts to decrease TPA sensitivity when inherited from C57BL/6. As predicted by Lee and Drinkwater (15) , the effects of Psl2, Psl3, and Psl4 on TPA promotion susceptibility are additive (Table 4)Citation . Mice inheriting the dominant sensitivity allele of both Psl2 and Psl3 have a significantly higher tumor multiplicity (P = 0.02) and are more sensitive to TPA than mice that inherit the dominant sensitivity allele of only one of these loci. In addition, inheritance of the dominant resistance allele of Psl4 results in decreased sensitivity to TPA. Because Psl1 does not segregate in the cross used in this study, we cannot analyze its effects on TPA sensitivity in combination with the other susceptibility loci described in this report. However, we would predict that mice inheriting the dominant allele of Psl1 would be more sensitive to TPA relative to mice with the same genotypes for Psl2, Psl3, and Psl4 but homozygous for the recessive allele of Psl1.

Analyses of (C57BL/6 x DBA/2)F1 x C57BL/6 and BxD RI mice also suggested tentative linkages of TPA promotion susceptibility loci to chromosomes 3, 4, 7, 8, 10, 13, 14, and 15. The failure to confirm linkages to these chromosomes in (C57BL/6 x BxD27)F2 mice does not rule out the possibility that TPA promotion susceptibility loci map to these regions. It is likely that BxD27 inherited some of these loci from C57BL/6. As a result, these loci would not segregate in this cross. Additional studies will be required to confirm the linkage of TPA promotion susceptibility loci to these chromosomal regions.

A number of potential candidate genes map near the TPA promotion susceptibility loci mapped in this report. These include genes that encode transcription factors (Tgfb2 on chromosome 1 and Cdc25b, Tcf15, and E2f1 on chromosome 2), proteins involved in apoptosis (Btg2 on chromosome 1 and Bcl2l on chromosome 2), members of the Ras protein family (Rgs7 on chromosome 1, Rasgrp1 and Rasl2–4 on chromosome 2, and Gprk5 on chromosome 19), laminin proteins (Lamc1, Lamc2, and Lamb3 on chromosome 1 and Lama5 on chromosome 2), metalloproteases (Adamts4 and Adam15 on chromosome 1 and Adam33 and Mmp24 on chromosome 2), phase I and phase II enzymes (Cyp2c29 and Cyp17 on chromosome 19 and Gstp-rs1 on chromosome 1), and tumor necrosis factor-associated proteins (Traf5 and Tnfsf6 on chromosome 1). Additional studies will be required to determine the role of these potential candidate genes in TPA promotion susceptibility.

In summary, we have mapped three novel TPA promotion susceptibility loci in (C57BL/6 x BxD27)F2 mice. Inheritance of the dominant allele of two of these loci, Psl2 and Psl3, results in increased sensitivity to TPA, whereas inheritance of the dominant allele of Psl4 results in decreased sensitivity. The dominant allele of Psl2 is inherited from the sensitive parent, and the dominant allele of Psl3 and Psl4 is inherited from the resistant C57BL/6 parent. The identification of additional loci, including a locus (Psl3) for which the dominant sensitivity allele is inherited from the resistant parent, is consistent with our genetic model of TPA promotion susceptibility (47) .


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by NIEHS Grant ES08355 (to J. D.), M. D. Anderson Cancer Center Core Grant CA16672, and NIEHS Center Grant ES07784. Back

2 To whom requests for reprints should be addressed, at The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, 1 Buescher Park Road, Smithville, TX 78957. Back

3 The abbreviations used are: TPA, 12-O-tetradecanoylphorbol-13-acetate; MNNG, N-methyl-N'-nitro-N-nitrosoguanidine; RI, recombinant inbred. Back

Received 9/ 3/02. Accepted 3/28/03.


   REFERENCES
Top
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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