ACTIVATION OF BP1 IS ACTIVATION OF BP1 IS ASSOCIATED WITH ASSOCIATED WITH
AGGRESSIVE BREAST AGGRESSIVE BREAST CANCERCANCER
PATRICIA BERG, PH.D.
pBP1 IS AN ISOFORM OF THE pBP1 IS AN ISOFORM OF THE DLX4 GENEDLX4 GENE
CHASE ET AL, 2002. MOL. CELL. BIOL. 22:2505-2514
NOTE: BP1 AND DLX4 ARE NOT INTERCHANGEABLE NOTE: BP1 AND DLX4 ARE NOT INTERCHANGEABLE TERMSTERMS
BP1BP1
DLX7DLX7
DLX4DLX4
CHARACTERISTICS OF BP1CHARACTERISTICS OF BP1
BELONGS TO THE DISTAL-LESS (DLX) FAMILY
DLX GENES ARE HIGHLY CONSERVED: FOUND IN DROSOPHILA, ZEBRAFISH, FROGS, CHICKENS, MICE AND HUMANS
IMPORTANT FOR CRANIOFACIAL, LIMB, TOOTH AND OCULAR DEVELOPMENT IN MICE
CHARACTERISTICS OF BP1CHARACTERISTICS OF BP1(CONT)(CONT)
ENCODES A TRANSCRIPTION FACTOR THAT REGULATES CASCADES OF GENES, INCLUDING ONCOGENES
A POTENTIAL ONCOGENE ACTIVATED IN A NUMBER OF DIFFERENT TYPES OF CANCER
ACTIVATION OF BP1 IN CANCERACTIVATION OF BP1 IN CANCER
BREAST CANCER – 80% (FU ET AL, 2003)
PROSTATE CANCER – 70% (SCHWARTZ ET AL, 2005)
ACUTE MYELOID LEUKEMIA – 63% (HAGA ET AL, 2000)
ACTIVATION OF BP1 IN CANCER ACTIVATION OF BP1 IN CANCER (CONT)(CONT)
OVARIAN CANCER – ~ 65% (and HARA ET AL, 2007)
LUNG CANCER – ~ 45% (and YU ET AL, 2008)
COLON CANCER – ~40%
Berg, PE and Kirolikar, S. 2011. Atlas Genet Cytogenet Oncol Haematol. 15: 658-661.
GENES INVOLVED IN NON-GENES INVOLVED IN NON-HEREDITARY BREAST CANCERHEREDITARY BREAST CANCER
GENE FREQUENCY
HER-2 20 – 30%
C-MYC 20 – 30%
CYCLIN E 30%
EGFR 25-35%
CYCLIN D1
BP1
50% (20% AMPLIFIED)
80%
ASSOCIATION BETWEEN BP1 mRNA EXPRESSION AND
CLINICO-PATHOLOGICAL DATA
BP1 mRNA Factors Negative Positive p value
ER Status 0.03Negative 0 (0%) 18 (100%)Positive 7 (27%) 19 (73%)
PR Status 0.02Negative 1 (4.0%) 24 (96%)Positive 6 (33%) 12 (67%)
Race 0.04Caucasian 6 (43%) 8 (57%)African American 3 (11%) 25 (89%)
FU et al, 2003. Br. Ca. Res. 5: 82-87.
BP1 AND BREAST CANCER BP1 AND BREAST CANCER PROGRESSIONPROGRESSION
MAN ET AL, 2005. BR. CA. RES. & TREAT. 90: 241-247.MAN ET AL, 2005. BR. CA. RES. & TREAT. 90: 241-247.
BP1 and ProgressionBP1 and ProgressionNORMAL
HYPERPLASIA (IDH)
DUCTAL CARCINOMA IN SITU (DCIS)
INVASIVE DUCTAL CARCINOMA (IDC)
0%
21%n=70
46% n=100
81% n=100
N
0% n=30
SUMMARYSUMMARY
AS TUMOR PROGRESSION OCCURS, THERE IS AN INCREASE IN
1. THE PERCENTAGE OF BP1 POSITIVE TUMORS
2. THE PERCENTAGE OF BP1 POSITIVE CELLS PER TUMOR
3. BP1 STAINING INTENSITY (BP1 EXPRESSION)
INFLAMMATORY BREAST INFLAMMATORY BREAST CANCERCANCER
RAPIDLY PROGRESSIVE HIGHLY ANGIOGENIC AND INVASIVE 5 YR SURVIVAL LESS THAN 45% VS 86% IN
NON-IBC LESS THAN HALF HAVE A DISCRETE MASS REPRESENT 1-5% OF ALL BREAST CANCERS
IN CAUCASIANS AND 10% IN AFRICAN AMERICANS
BP1 AND INFLAMMATORY BREAST BP1 AND INFLAMMATORY BREAST CANCERCANCER
100% OF IBC TUMORS WERE BP1 POSITIVE (N=45) WITH 95% OF CELLS POSITIVE
9 PAIRED METASTATIC LYMPH NODES AVAILABLE; ALL WERE BP1 POSITIVE
TUMOR CELLS IN BLOOD VESSELS AND LYMPHATIC CHANNELS WERE BP1 POSITIVE
Man et al, 2009. Ca. Biomarkers 5: 9-17. Man et al, 2009. Ca. Biomarkers 5: 9-17.
BP1 EXPRESSION IN LYMPHATIC BP1 EXPRESSION IN LYMPHATIC CHANNELS AND BLOOD VESSELSCHANNELS AND BLOOD VESSELS
LYMPHATIC CHANNELSLYMPHATIC CHANNELS BLOOD VESSELSBLOOD VESSELS
HOW IS BP1 ACTIVATED?HOW IS BP1 ACTIVATED?
A. A. DNA AMPLIFICATIONDNA AMPLIFICATION
B. ESTRADIOLB. ESTRADIOL
A. DNA AMPLIFICATIONA. DNA AMPLIFICATION
AMPLIFICATION OF BP1 WAS OBSERVED BY FISH IN 22% OF PRIMARY BREAST TUMORS AND IN 24% of MATCHED SLN METASTASES FROM PATIENTS WITH INVASIVE DUCTAL BREAST CANCER*
NOTE: BP1 MAPS TO 17Q21-22**
* * TORRESON ET AL, 2014; CAVALLI ET AL, 2008.TORRESON ET AL, 2014; CAVALLI ET AL, 2008.
** FU ET AL, 2001. GENE 278: 131-139. ** FU ET AL, 2001. GENE 278: 131-139.
FISH analysis of FFPE sections of a primary breast tumor (left) FISH analysis of FFPE sections of a primary breast tumor (left) and SLN metastasis (right) from one patient showing and SLN metastasis (right) from one patient showing
amplification of the amplification of the BP1BP1 gene gene
FISH ANALYSIS OF BP1FISH ANALYSIS OF BP1
CORRELATION BETWEEN BP1 CORRELATION BETWEEN BP1 AMPLIFICATION AND AMPLIFICATION AND
EXPRESSIONEXPRESSION
ALL CASES SHOWING BP1 AMPLIFICATION ALSO SHOWED BP1 EXPRESSION BY IHC
BP1 POSITIVITY WAS ALSO SEEN IN CASES WITHOUT AMPLIFICATION
BP1 AND HER2BP1 AND HER2
BP1 AND HER2 MAP NEAR EACH OTHER
AND ARE CO-AMPLIFIED 78% OF THE TIME IN PRIMARY TUMORS AND 100% OF THE
TIME IN SLN
B. ESTRADIOL STIMULATES BP1 IN MCF7 CELLS
ERα BINDS TO BP1 INTRON I
ChIPChIP
1. LADDER
2.3 INPUT CONTROL FOR ERE ELEMENT IN EXON I AND INTRON I
4.5 AFTER IP WITH ERα AB
BP1 ACTIVATES ONCOGENESBP1 ACTIVATES ONCOGENESGENE ASSOCIATED WITH
MMP9 INITIATION, INVASION, METASTASIS
BCL-2 ANTI-APOPTOTIC (Stevenson et al, 2007)
C-MYC PROLIFERATION, DIFFERENTIATION, APOPTOSIS
(Trinh et al, 2011)
MET
VEGF
GROWTH, ANGIOGENESIS, METASTASIS
ANGIOGENESIS (Hara et al, 2007)
BP1 EXPRESSION IS BP1 EXPRESSION IS ASSOCIATED WITH ASSOCIATED WITH AGGRESSIVENESS AGGRESSIVENESS
MEASURES OF AGGRESSIVENESSMEASURES OF AGGRESSIVENESS
BP1 INCREASES:BP1 INCREASES:
GROWTH IN THE ABSENCE OF SERUM
GROWTH IN SOFT AGAR (ANCHORAGE INDEPENDENT GROWTH)
INVASION THROUGH MATRIGEL
CHANGES IN TUMOR FORMATION IN NUDE MICE
O4
O2
V1
D4 D13
GROWTH IN SOFT AGARGROWTH IN SOFT AGAR
CELL LINES OVEREXPRESSING BP1 WERE CELL LINES OVEREXPRESSING BP1 WERE INJECTED INTO THE FAT PADS OF NUDE INJECTED INTO THE FAT PADS OF NUDE
MICEMICE
Submitted Submitted
EFFECT OF BP1 ON TUMOR EFFECT OF BP1 ON TUMOR GROWTH IN MICEGROWTH IN MICE
ESTROGEN INDEPENDENT ESTROGEN INDEPENDENT TUMOR FORMATION IN MICETUMOR FORMATION IN MICE
Cell Type Injected Estrogen added
Absence of Estrogen
MCF-7/EV-1 4/10 (40%) 0/10 (0%)
MCF-7/BP1-2 10/15 (67%) 2/10 (20%)
MCF-7/BP1-4 7/11 (64%) 2/10 (20%)
BP1 UPREGULATES ERBP1 UPREGULATES ERαα BOTH BOTH DIRECTLY AND INDIRECTLYDIRECTLY AND INDIRECTLY
SUBMITTEDSUBMITTED
DIRECT: BP1 ACTIVATES ERDIRECT: BP1 ACTIVATES ERαα RNA RNA BY BINDING TO IVS1BY BINDING TO IVS1
INDIRECT: BP1 STABILIZES ERINDIRECT: BP1 STABILIZES ERαα BY BY UPREGULATING p300 UPREGULATING p300
(p300 ACETYLATES ER(p300 ACETYLATES ERαα))
p300
ACTIN
O1V1
mRNAmRNA
PROTEINPROTEIN
INDIRECT: BP1 AND BRCA1INDIRECT: BP1 AND BRCA1
BRCA1 INHIBITS ERα PROTEIN VIA UBIQUITINATION
BP1 REPRESSES BRCA1 BY BINDING TO ITS FIRST INTRON (Kluk et al, 2010), WHICH IS PREDICTED TO FURTHER INCREASE THE LEVEL OF ERα
MODELMODEL
CONCLUSIONSCONCLUSIONS
BP1 EXPRESSION MAY BE PROGNOSTIC IN BREAST CANCER
BP1 IS A NEW POTENTIAL THERAPEUTIC TARGET
ACKNOWLEDGEMENTSACKNOWLEDGEMENTSGWUMCSAURABH KIROLIKAR JHUSANKET AWATE JUDITH KARPDANIEL RHEEY FARHAD VESUNABIN JIN HUANG VENU RAMANKELLIE YAMANEYASSI FALLAH AFIP YAN-GAO MANARNOLD SCHWARTZ PAUL LEVINE GEORGETOWN SAMUEL SIMMENS LUCIANE CAVALLISIDNEY FU
DAVID GEFFEN SOMNCIBARBARA JOSEPH PINZONE
VONDERHAAR
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