Abstract
BackgroundScaffold Attachment Factor B1 (SAFB1) is a multifunctional protein which has been implicated in breast cancer previously. We recently generated SAFB1 knockout mice (SAFB1-/-), but pleiotropic phenotypes including high lethality, dwarfism associated with low IGF-I levels, and infertility and subfertility in male and female mice, respectively, do not allow for straightforward tumorigenesis studies in these mice. Therefore, we asked whether SAFB1 heterozygosity would influence tumor development and progression in MMTV-Wnt-1 oncomice or DMBA induced tumorigenicity, in a manner consistent with haploinsufficiency of the remaining allele.MethodsWe crossed female SAFB1+/- (C57B6/129) mice with male MMTV-Wnt-1 (C57B6/SJL) mice to obtain SAFB1+/+/Wnt-1, SAFB1+/-/Wnt-1, and SAFB1+/- mice. For the chemical induced tumorigenesis study we treated 8 weeks old SAFB1+/- and SAFB+/+ BALB/c mice with 1 mg DMBA once per week for 6 weeks. Animals were monitored for tumor incidence and tumor growth. Tumors were characterized by performing H&E, and by staining for markers of proliferation and apoptosis.ResultsWe did not detect significant differences in tumor incidence and growth between SAFB1+/+/Wnt-1 and SAFB1+/-/Wnt-1 mice, and between DMBA-treated SAFB1+/+ and SAFB1+/-mice. Histological evaluation of tumors showed that SAFB1 heterozygosity did not lead to changes in proliferation or apoptosis. There were, however, significant differences in the distribution of tumor histologies with an increase in papillary and cribriform tumors, and a decrease in squamous tumors in the SAFB1+/-/Wnt-1 compared to the SAFB1+/+/Wnt-1 tumors. Of note, DMBA treatment resulted in shortened survival of SAFB1+/- mice compared to their wildtype littermates, however this trend did not reach statistical significance.ConclusionOur data show that SAFB1 heterozygosity does not influence Wnt-1 or DMBA-induced mammary tumorigenesis.
Highlights
Scaffold Attachment Factor B1 (SAFB1) is a multifunctional protein which has been implicated in breast cancer previously
SAFB1 protein expression is decreased in SAFB1+/- mice First, we set out to confirm decreased SAFB1 protein levels in SAFB1+/- mice using a number of different tissues, including testes, spleen, lung, and mammary gland (Figure 1A)
Quantification revealed an average decrease of 42% in the SAFB1+/- mice, compared to SAFB1+/+ mice (Figure 1B)
Summary
Scaffold Attachment Factor B1 (SAFB1) is a multifunctional protein which has been implicated in breast cancer previously. There is no significant different in LOH frequencies between ER-positive and ERnegative tumors, and other in vitro observations [4] suggest that SAFB1 could exert its effect on tumorigenesis, at least in part, through ER-independent mechanisms. This is further supported by our recent observation that loss of SAFB1/SAFB1 is associated with worse overall survival of breast cancer patients, but does affect Tamoxifen response [5]. These data suggest that SAFB1 loss affects breast tumorigenesis in ER-dependent and independent manner
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