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Immunization against HIF-1? Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

ABSTRACT: Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell-enriched phenotype. Hypoxia-inducible factor-1? (HIF-1?) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1? was immunogenic and whether vaccination targeting HIF-1? would impact the growth of basal-like mammary tumors in transgenic mice.Experimental Design: We evaluated HIF-1?-specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1? protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1? Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1? and stem cells in the tumor were quantitated by Western blotting and flow cytometry.Results: The magnitude (P < 0.001) and incidence (P < 0.001) of HIF-1?-specific IgG were elevated in TNBC patients compared with controls. Both breast cancer patients and donors showed evidence of HIF-1?-specific Th1 and Th2 immunity. Three HIF-1?-specific Th1 class II restricted epitopes that were highly homologous between species elicited type I immunity in mice. After HIF-1? vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh; P < 0.001) not TgMMTV-neu (luminal/neu/stem celllow; P = 0.859) murine models. Vaccination increased type I T cells in the tumor (P = 0.001) and decreased cells expressing the stem cell marker, Sca-1, compared with controls (P = 0.004).Conclusions: An HIF-1? vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence. Clin Cancer Res; 23(13); 3396-404. ©2016 AACR.

SUBMITTER: Cecil DL

PROVIDER: S-EPMC5493515 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

Cecil Denise L DL Slota Meredith M O'Meara Megan M MM Curtis Benjamin C BC Gad Ekram E Dang Yushe Y Herendeen Daniel D Rastetter Lauren L Disis Mary L ML

Clinical cancer research : an official journal of the American Association for Cancer Research 20161230 13

Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell-enriched phenotype. Hypoxia-inducible factor-1α (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice.Experimental Design: We evaluated HIF-1α-specific IgG in sera from controls and patients with breast ...[more]

PMID: 28039264

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Project description:Purpose: GATA3 is a transcription factor essential for mammary luminal epithelial cell differentiation. Expression of GATA3 is absent or significantly reduced in basal-like breast cancers. Gata3 loss-of-function impairs cell proliferation, making it difficult to investigate the role of GATA3 deficiency in vivo. We previously demonstrated that CDK inhibitor p18INK4c (p18) is a downstream target of GATA3 and restrains mammary epithelial cell proliferation and tumorigenesis. Whether and how loss-of-function of GATA3 results in basal-like breast cancers remains elusive. Methods: We generated mutant mouse strains with heterozygous germline deletion of Gata3 in p18 deficient backgrounds and developed a Gata3 depleted mammary tumor model system to determine the role of Gata3 loss in controlling cell proliferation and aberrant differentiation in mammary tumor development and progression. Results: Haploid loss of Gata3 reduced mammary epithelial cell proliferation with induction of p18, impaired luminal differentiation, and promoted basal differentiation in mammary glands. p18 deficiency induced luminal type mammary tumors and rescued the proliferative defect caused by haploid loss of Gata3. Haploid loss of Gata3 accelerated p18 deficient mammary tumor development and changed the properties of these tumors, resulting in their malignant and luminal-to-basal transformation. Expression of Gata3 negatively correlated with basal differentiation markers in MMTV-PyMT mammary tumor cells. Depletion of Gata3 in luminal tumor cells also reduced cell proliferation with induction of p18 and promoted basal differentiation. We confirmed that expression of GATA3 and basal markers are inversely correlated in human basal-like breast cancers. Conclusions: This study provides the first genetic evidence demonstrating that loss-of-function of GATA3 directly induces basal-like breast cancer. Our finding suggests that basal-like breast cancer may also originate from luminal type cancer.

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Immunization against HIF-1? Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo.

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Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells <i>In Vivo</i>.

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