Aberrant expression of DNA damage response proteins is associated with breast cancer subtype and clinical features

Abstract

Landmark studies of the status of DNA damage checkpoints and associated repair functions in preneoplastic and neoplastic cells has focused attention on importance of these pathways in cancer development, and inhibitors of repair pathways are in clinical trials for treatment of triple negative breast cancer. Cancer heterogeneity suggests that specific cancer subtypes will have distinct mechanisms of DNA damage survival, dependent on biological context. In this study, status of DNA damage response (DDR)-associated proteins was examined in breast cancer subtypes in association with clinical features; 479 breast cancers were examined for expression of DDR proteins γH2AX, BRCA1, pChk2, and p53, DNA damage-sensitive tumor suppressors Fhit and Wwox, and Wwox-interacting proteins Ap2α, Ap2γ, ErbB4, and correlations among proteins, tumor subtypes, and clinical features were assessed. In a multivariable model, triple negative cancers showed significantly reduced Fhit and Wwox, increased p53 and Ap2γ protein expression, and were significantly more likely than other subtype tumors to exhibit aberrant expression of two or more DDR-associated proteins. Disease-free survival was associated with subtype, Fhit and membrane ErbB4 expression level and aberrant expression of multiple DDR-associated proteins. These results suggest that definition of specific DNA repair and checkpoint defects in subgroups of triple negative cancer might identify new treatment targets. Expression of Wwox and its interactor, ErbB4, was highly significantly reduced in metastatic tissues vs. matched primary tissues, suggesting that Wwox signal pathway loss contributes to lymph node metastasis, perhaps by allowing survival of tumor cells that have detached from basement membranes, as proposed for the role of Wwox in ovarian cancer spread.

DNA damage and breast cancer

“…We will present a detailed discussion of the role of two DNA damage response genes, BRCA1 and BRIT-1 as well as briefly discussing PARP-1. Aberrant DNA damage response gene expression is common in nearly all breast cancer phenotypes [4] . In the last decade, genetic and clinical studies have described several sub-types of breast cancers based upon hormone and growth factor receptor status [5] ; genomic descriptions of cancer cell sub-types (Luminal A, Luminal B, Basal-like, HER2+) which have been the basis of modified models of breast cancer development [1] ; or protein expression descriptions such as HER2-overexpressed or Claudin-low.…”

“…In the last decade, genetic and clinical studies have described several sub-types of breast cancers based upon hormone and growth factor receptor status [5] ; genomic descriptions of cancer cell sub-types (Luminal A, Luminal B, Basal-like, HER2+) which have been the basis of modified models of breast cancer development [1] ; or protein expression descriptions such as HER2-overexpressed or Claudin-low. With the diversity of these classification schemes it is still true that a commonality among breast cancers is a defect in DNA damage repair and BRCA1 inactivation through mutation or epigenetic modification is very common [4,6,7] . We may start our dissection of breast cancer phenotypes with two broad classifications, i.e.…”

“…Most often these tumor suppressor genes are involved with maintenance of DNA fidelity as is the case for BRCA1 (DNA damage repair), TP53 (cell cycle checkpoint) and PTEN (blockage of cell-cycle progression in G1 and participation in DNA repair). The genes involved in heritable susceptibility to cancer often function as DNA damage response effectors or cell cycle control effectors [4,9] . Inherited breast cancers occur early and in pre-menopausal years because of the increased risk of loss of heterozygosity, and thus loss of gene expression of a DNA damage response or cell cycle control effector gene product [6,10] .…”

“…In sporadic breast cancer-the majority of breast cancers-an acquired mutation or epigenetic inactivation occurs due to mechanisms other than inheritance of defective genetic material. Again many of these mutations or epigenetic inactivations occur within genes involved in DNA damage repair [4,6] . A second method of breast cancer classification is based upon hormone receptor (in particular estrogen and progesterone receptors) and epidermal growth factor receptor (HER-2 specifically) positivity.…”

“…In this particular classification scheme, estrogen receptor (ER), progesterone receptor and ErbB2/HER2 classification is divided into: (1) hormone receptor positive; (2) hormone receptor negative with HER2 over-expression; and (3) "triple negative" (breast cancer which does not express any of the three receptors) [5,12] . Triple-negative breast cancers often contain inactivation of the DNA repair gene BRCA1 [4][5][6][7]9,12] . In fact, as much as 30% of breast cancers are thought to have some degree of BRCA1 inactivation [9] .…”