METHODS OF DETECTING BREAST CANCER BRAIN METASTASIS WITH GENOMIC AND EPIGENOMIC BIOMARKERS

1 . A method for diagnosing a breast cancer central nervous system (CNS) metastasis in a subject, comprising:

a) determining the expression level of at least one gene selected from the group consisting of ATAD2, BRAF, DERL1, DNMTRB, NEK2A, AKT1, AURKA, AURKB, ESR2, FASN, FOXM1, TBX2, TNFRSF12A, PSENEN, HIF1A, IGF1R, MCL1, PPFIA1, RAF1, PRL, RXRA, SRD5A2, SUMO2, TYMS, UBA1, VEGFA, WNT3A, HOXA7, HOXA9, HOXA10, HOXA11, ERBB2, NEUROD2, and WNT9A in a subject-derived brain or breast tissue;

b) comparing the subject-derived expression level determined in step a) with a normal control level obtained from normal brain or breast cells; and

c) correlating an increase of said subject-derived expression level as compared to the normal control level to a diagnosis of a breast cancer CNS metastasis.

2 . The method of claim 1 , wherein the at least one gene is selected from the group consisting of FOXM1, AURKB, and ATAD2.

3 . The method of claim 2 , wherein expression is determined with quantitative reverse-transcriptase (RT)-PCR.

4 . The method of claim 3 , wherein the quantitative RT-PCR comprises amplification of nucleic acids from the breast or brain tissue with a primer comprising a sequence selected from the group consisting of SEQ ID NO:1, SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, and SEQ ID NO:6.

5 . A method for diagnosing a breast cancer CNS metastasis in a subject, comprising:

a) determining the expression level of at least one gene selected from the group consisting of CTNNA3, ATM, TCF4, CDKN2A, CDKN2B, MSH6, RB1, RPS6KA3, CRYAB, HSPB2, and DMRTA1 in a subject-derived brain or breast tissue;

b) comparing the subject-derived expression level determined in step a) with a normal control level obtained from normal brain or breast cells; and

c) correlating a decrease of said subject-derived expression level as compared to the normal control level to a diagnosis of a breast cancer CNS metastasis.

6 . A method for the treatment of a breast cancer CNS metastasis in a subject comprising administering to the subject an inhibitor of a gene selected from the group consisting of ATAD2, BRAF, DERL1, DNMTRB, NEK2A, AKT1, AURKA, AURKB, ESR2, FASN, FOXM1, TBX2, TNFRSF12A, PSENEN, HIF1A, IGF1R, MCL1, PPFIA1, RAF1, PRL, RXRA, SRD5A2, SUMO2, TYMS, UBA1, VEGFA, WNT3A, HOXA7, HOXA9, HOXA10, HOXA11, ERBB2, NEUROD2, and WNT9A.

7 . The method of claim 6 , wherein the inhibitor is selected from the group consisting of a chemical agent, an antibody, and an siRNA molecule.

8 . The method of claim 6 , wherein the gene is ATAD2.

9 . A method for the treatment of a breast cancer CNS metastasis in a subject comprising administering to the subject at least one compound selected from the group consisting of Vidaza, Entinostat, and a PARP inhibitor.

10 . The method of claim 9 , wherein the PARP inhibitor is selected from the group consisting of Iniparib, Olaparib, Rucaparib, Veliparib, CEP 9722, MK 4827, BMN-673, and 3-aminobenzamide.

11 . The method of claim 9 wherein Vidaza and the PARP inhibitor are administered to the subject.

12 . A method for diagnosing a breast cancer CNS metastasis in a subject, comprising:

a) determining a methylation level of at least one gene selected from the group consisting of EDNRB, RUNX3, RELN, BANK1, CDKN1, ITGAM, EDN3, and PENK in a subject-derived brain or breast tissue;

b) comparing the subject-derived methylation level determined in step a) with a normal control level obtained from normal brain or breast cells; and

c) correlating an increase of said subject-derived methylation level as compared to the normal control level to a diagnosis of a breast cancer CNS metastasis.

13 . The method of claim 12 , wherein in the at least one gene is BANK1 or CDKN1.

14 . The method of claim 12 , wherein the subject has been diagnosed with a breast cancer molecular subtype of Luminal B.

15 . The method of claim 12 , wherein the methylation level is determined with bisulfite treatment of DNA, reverse phase high pressure liquid chromatography (HPLC), methylation sensitive PCR (MSP), bisulfite PCR, cloning differentially methylated sequences, Southern blot analysis, methylated CpG island amplification (MCA), differential methylation hybridization using CpG island arrays, isolation of CpG islands using a CpG binding column, DNA-methyltransferase assay, bisulfite modification, bisulfite pyrosequencing, methylation detection after restriction, methylation-sensitive restriction fingerprinting, restriction landmark genomic scanning (RLGS), or bisulfite conversion combined with bisulfite restriction analysis (COBRA).

16 . The method of claim 15 , wherein the methylation level is determined with bisulfite pyrosequencing.

17 . A method for diagnosing a breast cancer CNS metastasis in a subject, comprising:

a) determining the methylation level of at least one gene selected from the group consisting of KRT8, ALDH1A3, FANCG, TRIM29 and HOXA11 in a subject-derived brain or breast tissue;

b) comparing the subject-derived methylation level determined in step a) with a normal control level obtained from normal brain or breast cells; and

c) correlating a decrease of said subject-derived methylation level as compared to the normal control level to a diagnosis of a breast cancer CNS metastasis.

18 . The method of claim 17 , wherein the at least one gene is KRT8.

19 . The method of claim 17 , wherein the subject has been diagnosed with a breast cancer molecular subtype of basal-like.

20 . The method of claim 17 , wherein the methylation level is determined with bisulfite treatment of DNA, reverse phase HPLC, MSP, bisulfite PCR, cloning differentially methylated sequences, Southern blot analysis, MCA, differential methylation hybridization using CpG island arrays, isolation of CpG islands using a CpG binding column, DNA-methyltransferase assay, bisulfite modification, bisulfite pyrosequencing, methylation detection after restriction, methylation-sensitive restriction fingerprinting, RLGS, or COBRA.