Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues

Bernatsky, Sasha; Easton, DF; Dunning, Alison M.; Michailidou, Kyriaki; Ramsey‐Goldman, Rosalind; Gordon, Caroline; Clarke, A.; Foulkes, William D.

doi:10.1177/0961203312443992

Cited by 26 publications

(19 citation statements)

References 19 publications

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“…Earlier, we used general population breast cancer genome-wide association study (GWAS) data, to explore whether single nucleotide polymorphisms (SNPs) predisposing to SLE might be protective against breast cancer (in women in the general population)[19]. We focused on loci relevant to 10 SNPs that are highly associated with SLE.…”

Section: Discussionmentioning

confidence: 99%

Breast cancer in systemic lupus

Bernatsky

Ramsey‐Goldman

Petri

et al. 2016

Lupus

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Objective There is a decreased breast cancer risk in SLE versus the general population. We assessed a large sample of SLE patients, evaluating demographic and clinical characteristics and breast cancer risk. Methods We performed case-cohort analyses within a multi-centre international SLE sample. We calculated the breast cancer hazard ratio (HR) in female SLE patients, relative to demographics, reproductive history, family history of breast cancer, and time-dependent measures of anti-dsDNA positivity, cumulative disease activity, and drugs, adjusted for SLE duration. Results There were 86 SLE breast cancers and 4,498 female SLE cancer-free controls. Patients were followed on average for 7.6 years. Versus controls, SLE breast cancer cases tended to be white and older. Breast cancer cases were similar to controls regarding anti-dsDNA positivity, disease activity and most drug exposures over time. In univariate and multivariate models, the principal factor associated with breast cancers was older age at cohort entry. Conclusions There was little evidence that breast cancer risk in this SLE sample was strongly driven by any of the clinical factors that we studied. Further search for factors that determine the lower risk of breast cancer in SLE may be warranted.

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Section: Discussionmentioning

confidence: 99%

Breast cancer in systemic lupus

Bernatsky

Ramsey‐Goldman

Petri

et al. 2016

Lupus

Self Cite

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“…However, the influence of chronic autoimmunity on the natural history of solid tumors is not well understood. For example, although SLE patients have decreased risk of breast cancer and melanoma (23), the underlying mechanisms and biological significance of these observations are unclear. It may be relevant that longitudinal analyses of sera from long-term surviving melanoma patients after vaccination with GM-CSF-secreting autologous melanoma cells have revealed that the generation of autoantibodies was associated with increased tumor destruction (15).…”

Section: Discussionmentioning

confidence: 99%

Disruption of CD8+ Treg Activity Results in Expansion of T Follicular Helper Cells and Enhanced Antitumor Immunity

Arias

Kim

Zhou

et al. 2014

Cancer Immunology Research

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Tumor growth is associated with the inhibition of host antitumor immune responses that can impose serious obstacles to cancer immunotherapy. To define the potential contribution of Qa-1-restricted CD8 regulatory T cells (Treg) to the development of tumor immunity, we studied B6.Qa-1 D227K mice that harbor a point mutation in the MHC class Ib molecule Qa-1 that impairs the CD8 Treg suppressive activity. Here, we report that growth of B16 melanoma is substantially delayed in these Qa-1 mutant mice after therapeutic immunization with B16 melanoma cells engineered to express GM-CSF compared to Qa-1 B6.WT controls. Reduced tumor growth is associated with the enhanced expansion of follicular T helper cells, germinal center B cells, and high titers of antitumor autoantibodies, which provoke robust antitumor immune responses in concert with tumor-specific cytolytic T cells. Analysis of tumor-infiltrating T-cells revealed that the Qa-1 DK mutation was associated with an increase in the ratio of CD8+ T effectors compared with CD8 Treg cells. These data suggest that the CD8+ T effector–Treg ratio may provide a useful prognostic index for cancer development and raise the possibility that depletion or inactivation of CD8 Treg represents a potentially effective strategy to enhance antitumor immunity.

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“…SLE is associated with an overall increased risk of malignancy, but lower than expected rates of tumors associated with defects in BRCA2 such as breast, ovarian, and prostate cancers141516. The pathophysiology underlying this risk profile is unknown and is likely multifactorial1718. We previously suggested that cell-penetrating lupus autoantibodies such as 3E10 that inhibit DNA repair might contribute to this phenomenon by suppressing growth of BRCA2- cells6, and our present findings now raise the possibility that nucleolytic lupus autoantibodies may also contribute to inhibiting the growth of BRCA2-associated tumors in patients with SLE.…”

Section: Discussionmentioning

confidence: 99%

A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells

Noble

Young

Bernatsky

et al. 2014

Sci Rep

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Cancer cells with defects in DNA repair are highly susceptible to DNA-damaging agents, but delivery of therapeutic agents into cell nuclei can be challenging. A subset of lupus autoantibodies is associated with nucleolytic activity, and some of these antibodies are capable of nuclear penetration. We hypothesized that such antibodies might have potential as therapeutic agents targeted towards DNA repair-deficient malignancies. We identified the lupus autoantibody 5C6 as a cell-penetrating nucleolytic antibody and found that 5C6 has a differential effect on a matched pair of BRCA2-proficient and deficient DLD1 colon cancer cells. 5C6 selectively induced γH2AX in, and suppressed the growth of, the BRCA2-deficient cells. These findings demonstrate the potential utility of 5C6 in targeted therapy for DNA repair-deficient malignancies and strengthen the rationale for studies of additional lupus autoantibodies in order to identify the best candidates for development as therapeutic agents. In addition, the toxic effect of 5C6 on BRCA2-deficient cells provides further support for the hypothesis that some lupus autoantibodies contribute to the lower risk of specific cancers associated with systemic lupus erythematosus.

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Decreased breast cancer risk in systemic lupus erythematosus: the search for a genetic basis continues

Abstract: Within this large breast cancer dataset, we did not demonstrate important associations with 10 lupus-associated SNPs. If decreased breast cancer risk in SLE is influenced by genetic profiles, this may be due to complex interactions and/or epigenetic factors.

Cited by 26 publications

References 19 publications

Breast cancer in systemic lupus

Breast cancer in systemic lupus

Disruption of CD8+ Treg Activity Results in Expansion of T Follicular Helper Cells and Enhanced Antitumor Immunity

A nucleolytic lupus autoantibody is toxic to BRCA2-deficient cancer cells

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