Commonalities and differences between hormonal pathways in breast, endometrium and prostate cancer

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Commonalities and differences between hormonal
pathways in breast, endometrium and prostate
cancer

• Rob, Angel, Isaac, Zenon, Crina
• InfoBiomed 2nd Training Challenge
• Les Avellanes, 2006

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Cancer stages
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Hormone sensitive cancers
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Medical focus
Genetic factors BC BRCA1, BRCA2 PC BRCA1,
BRCA2, RNASEL, HPC1 MXI1
Environmental Diet high fat, low
vegetables Ethnicity BC-caucasian PC
afro-american Family history tumours 1degree
relative Age BCgt35, PCgt45y
Hormonal factorsincrease steroid
hormone Estrogen, Progesteron, Androgen
BC, EC early menarche late menopause EC
nuliparity infertility
Breast cancer/endometrium cancer Prostate cancer
Breast cancer cell ER-A, ER-B initiate,
promotion PR-A, PR-B BRCA1 role -coactivate
p53 -modulate p300/cPB expression -ligand
corepressor for ER, AR, PR
Prostate cancer cell AR ER-B highly
expressed ER-A BRCA1, BRCA2, RNASEL, HPC1 MXI1,
KAI1, PCAP, HPCX
Estrogen cancer cell ER-A, ER-B expression (for
70-80) PR PAX2 expression
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Why look for similarities?

• Prostate, breast and endometrial cancers have
  frequently maintained hormone sensitivity.
  Treatments are similar as well as disease
  progression.
• The hormone receptors involved are of the same
  family the nuclear hormone receptors. The
  involved hormones are similar.

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Nuclear Hormone Receptors

• Androgen, Estrogen and Progesterone Receptors

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How can computers help?
Genome Databases Ensembl GenAtlas GeneCard UniGene
EntrezGeneGDB
Plant genomics DNA sequecing Protein modeling
Clinical DB PubMed Cohrane Embase OMIM Syst.review
/meta-analysis?
Sequence analysis Tool Blast Find common
sequences among genes EMBL
Model organism databases GDB, MGI
Proteomics/Expression data? Microarray
analysis Protein modelling Find protein structure
pitfalls
Metabolic pathways databases Modeling steroid
pathways Tool SBML
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What information is available

• Literature
• Microarray data
• Sequence data
• Protein Structure data
• Ligand specificity data
• etc.

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The Team

• Crina medicine, data mining
• Rob molecular biology and text mining
• Isaac bioinformatics, sequence analysis,
  protein-protein interactions
• Angel bioinformatics, microarray analysis
• Zenon informatics, statistical analysis

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Objectives

• Develop research set-up to find similarities
  and/or differences between the three cancers and
  NHR receptor pathways.
• Assess the usefulness of this approach.

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The Approach in General

• Detect patterns of similarity
• High throughput data, e.g. microarray data
  analysis of cancer stages or NHR stimulation.
• Transfer of knowledge
• E.g. co-regulators of NHRs, such as SRC1, show
  frequent cross-reactivity and some are involved
  in the development of cancer.

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Patterns of Similarity

• DNA microarray data stimulation of the estrogen,
  androgen and progesterone receptors.
• Co-expression
• Genomic co-location
• Gene ontologies
• Protein-Protein Interaction data

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Patterns of Similarity data analysis

• Step 1 Making the heterogeneous datasets
  comparable.

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Patterns of Similarity co-location

• Are there areas on the genome that show a
  remarkable difference in transcription activity
  following the stimulation of the three NHRs?
• Genomic instability in these regions maybe
  important in cancer progression.
• Link to CGH data

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Comparative Genomic Hybridization (CGH)

• A molecular cytogenetic method of screening a
  tumor for genetic changes. The alterations are
  classified as DNA gains and losses and reveal a
  characteristic pattern that includes mutations at
  chromosomal and subchromosomal levels.

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Transfer of Knowledge

• Which genes interact with the Estrogen Receptor?
• Literature and pathway databases

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Transfer of Knowledge

• General model of NHRs
• amino-terminal activation
• DNA-binding domain
• carboxy-terminal ligand binding domain,
  containing second activation function
• without ligand sequestered with a.o. heat shock
  proteins
• with ligand series of events leading to binding
  to hormone-response elements in the regulatory
  regions of genes.

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Transfer of Knowledge
Infobiomed WP6.1
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Transfer of Knowledge Finding a candidate
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Transfer of Knowledge PELP1

• Coregulator of ER
• Association to BC recent (2005)
• New mechanism (cytoplasmic location of PELP1) to
  tamoxifen resistance.

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Transfer of Knowledge PELP1

• Is PELP1 also involved in AR activity regulation?
• Could there be another protein fulfilling a
  similar role?

BRCA3
RAL14
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Lessons Learned

• Working in a interdisciplinary team is
  difficult.
• Communication is a hard skill to learn
• Forming a team requires patience not ambition.
• The more difficult the challenge, the more
  rewarding.

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• So the final list we obtained was this
• - Most relevant genes and proteins implicated in
  the estrogen nuclear receptor pathway ? ESR1,
  ESR2, BRCA1, BRCA2, BRCA3, HDAC1, PPARGC1A,
  EP300, CCND1, PELP1, LIV-1, N-CoA2, N-CoR2, REA,
  MRP1.
• - Most relevant genes and proteins implicated in
  the progesterone nuclear receptor pathway ? PRA,
  PRB, E6-AP, RPF1, L7/SPA, CBP, P300, N-CoR, SMRT,
  Uba3, RTA.
• - Most relevant genes and proteins implicated in
  the androgen nuclear receptor pathway ?
  cytokeratins 5,8,14,18,19, P63, chromogramin A,
  Synaptophysin, inhibins A and B, activins A,AB,
  and B, FGF7, FGF10, Ptc associated to Shh
  receptors, RNASEL, HPC1, MXI1, KAI1, PCAP, HPCX,
  CAPB, HPC2/ELAC2, PTEN, MAD1L1, ATBF1, PRCA1,
  KLF6, CHEK2, EPHB2, CDH1.

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• - Most relevant genes and proteins related with
  breast cancer ? BRMS1L, LIV-1, BRCA3, RAL14,
  CNN3, STMN4, TRPV1, PDLIM7, ACTN1, CYR61, TPM1.
• Most relevant genes and proteins related with
  prostate cancer ? PCTA-1, ICK, TMEPAI, HMGN2,
  MYLK, COL4A1, EIF3S6IP.
• - Its very difficult to find information about
  endometrium cancer so the most relevant genes and
  proteins we have found are only ? ESR1, ESR2, PGR.

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• PELP1 is a gene that encodes a protein
  (proline-, glutamic acid-, leucine-rich protein
  1) with the same name (PELP1) which acts as a
  novel human coregulator of estrogen receptor
  alpha.
• We choose this gene because it is expressed in
  the estrogen receptor pathway of breast cancer,
  but not in prostate and endometrium cancer and
  also because it appears many times in the
  literature so it may be an important gene.

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• PELP1 protein binds to the estrogen receptor to
  coactivate the receptor and it also binds with
  three important cell proteins like BAT3 (large
  proline-rich protein), SUMO2 (small
  ubiquitin-related modifier 2 precursor) and TM1L1
  (TOM1-like 1 protein )

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• PELP1 functioned as a coactivator of RXRalpha
  (estrogen receptor alpha), increasing its
  transactivation function.
• BAT3 is a nuclear protein that has been
  implicated in apoptosis.
• SUMO-2 strongly enhance transactivation by
  endogenous androgen receptor.
• Function of TOM1 remain unknown. Is already
  proposed that TOM1 is another member of a family
  of genes implicated in the trafficking regulation
  of growth-factor-receptor complexes that are
  destined for degradation in the lysosome
• Why is PELP1 acting in breast cancer and not in
  prostate and endometrium cancer?
• Are maybe other proteins in prostate and
  endometrium cancer doing the function of PELP1 in
  breast cancer?