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Presented By: Anvita Jadhav 
Final Year B.Pharm 
29/11/2013 
1
Anatomy of the Female Breast 
Clavicle 
Second Rib 
Pectorals Major Muscle 
Fat 
Lactiferous Sinus 
Lactiferous Duct 
Glan...
Breast Carcinoma 
Non-invasive Carcinoma Invasive Carcinoma 
a) Invasive Duct Carcinoma: 70% cases. 
b) Invasive Lobular C...
Receptor Overexpression Specific for Breast Cancer 
Receptors 
Hormone 
receptor 
(HR) 
ER 
ER+ve ER-ve 
PR 
PR+ve PR-ve 
...
Globally, Breast cancer accounts for 23% of the total cancer cases and 14% of the 
cancer deaths in females. 
The cases ar...
Treatments 
Surgery 
Radiotherapy 
Hormonal therapy 
Chemotherapy 
6
Targeted Cancer Therapies 
Drugs or other substances that block the growth and spread of cancer by 
interfering with speci...
In this seminar, we are going to study breast cancer therapies which are targeted 
for following targets: 
Tyrosine Kinase...
Tyrosine Kinases (TKs) 
 Class of enzymes which are responsible for phosphorylation of tyrosine residue on 
targeted prot...
mTOR/PI3K/Akt 
Pathway 
IP3/DAG Pathway 
Ras/MAPK 
Pathway 
Multiple signaling pathways involved in the development, growt...
Human Epidermal Receptors (HER) 
o ErbB proteins are a four-member family of highly homologous receptor tyrosine kinases 
...
Human Epidermal Receptor 2(HER2) 
The HER2 gene is amplified in approximately 20%-30% of breast cancers. 
Overexpression H...
Trastuzumab Trastuzumab DM 1 
13
Selected HER Family Tyrosine Kinase Inhibitors: 
Compound Selectivity invitro IC(Nm) Stages 
EGFR HER2 
ZD1839, Gefitinib ...
Insulin-like Growth Factor Receptor (IGFR) 
IGF system is composed of 
IGF 
system 
Ligands 
IGF1 IGF2 
Receptors 
IGF1R I...
Insulin-like growth factor 1 receptor (IGF-1R) Targeting Agents: 
Agents Regimen Stages 
IGF-1R Antibodies 
CP-751,871 Doc...
Fibroblast Growth Factor Receptor (FGFR) 
The fibroblast growth factor (FGF) consist of 18 ligands. 
FGF1 & FGF23 signal t...
Drug class Drug name Target Stages 
1st generation 
TKI258 (Dovitinib) FGFR, PDGFR & 
TKIs 
VEGFR 
Phase III 
BMS54021 (Br...
Drug class Drug name Target Stages 
2nd generation 
AZD 4547 Selective FGFR1, 
TKIs 
FGFR2 & FGFR3 
inhibitor 
Phase II 
B...
Vascular Endothelial Growth Factor (VEGF) 
 VEGF overexpression is common in breast cancer. 
 Bevacizumab (Avastin; Gene...
Platelet Derived Growth Factor (PDGFR) 
PDGFR is expressed in most breast tumors. 
The individual PDGF chains have differe...
Steroid Receptor Coactivators (SRCs) 
SRCs are small proteins of 160 kDa non-receptor tyrosine kinase and include SRC-1, 
...
Mammalian Target of Rapamycin (mTOR) 
mTOR is a member of the cellular mTOR/PI3K/Akt pathway. A high proportion of breast...
The mTOR/PI3K/Akt pathway 
PI3K inhibitor 
24
mTOR inhibitors: 
Drug Drug class Stage of development 
Sirolimus 
(Rapamycin) 
mTOR inhibitor Approved 
Everolimus 
(RAD0...
Sirolimus (Rapamycin) 
Everolimus 26
PI3K selective inhibitors: 
Agents Company Stage 
PX-866 Oncothyreon Inc Phase I 
GDC-0941 Genentech Inc Phase II 
XL-147 ...
Dual kinase (mTOR &PI3K) inhibitors: 
Drug Drug class Stage of development 
PI-103 Dual kinase inhibitor Preclinical 
LY29...
Poly-{Adenosine diphosphate (ADP)-Ribose} Polymerase (PARP) 
DNA damage, double strand breaks are highly toxic to cells 
...
PARP-inhibitors in clinical development: 
Agent Company Stages 
Olaparib (AZD2281) AstraZeneca/KuDOS Phase I/II 
Veliparib...
Conclusion 
Targeted cancer therapies hold the promise of being more selective, reducing side 
effects, and improving qual...
References: 
1) Harsh Mohan, Chapter 25 The Breast, Textbook of Pathology, Jaypee Brothers Medical Publishers Pvt. Ltd., 6...
References: 
9) Hetty Carraway and Manuel Hidalgo, New targets for therapy in breast cancer: Mammalian target of 
rapamyci...
References: 
17) Ahmedin Jemal, Freddie Bray, Melissa M. Center, Jacques Ferlay, Elizabeth Ward, and David Forman, Global ...
Thank You 
35
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Targeted Therapies for Breast Cancer

Targeted therapies for breast cancer

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Targeted Therapies for Breast Cancer

  1. 1. Presented By: Anvita Jadhav Final Year B.Pharm 29/11/2013 1
  2. 2. Anatomy of the Female Breast Clavicle Second Rib Pectorals Major Muscle Fat Lactiferous Sinus Lactiferous Duct Gland Lobules Fat The breast is a modified skin appendages which functions in the females during lactation. There are two types of tissue components: Epithelial and Stromal 2
  3. 3. Breast Carcinoma Non-invasive Carcinoma Invasive Carcinoma a) Invasive Duct Carcinoma: 70% cases. b) Invasive Lobular Carcinoma: 5% cases. c) Medullary Carcinoma: 1% cases. d) Colloid Carcinoma e) Papillary Carcinoma f) Tubular Carcinoma: g) Adenoid Cystic Carcinoma h) Secretory (Juvenile) Carcinoma i) Inflammatory Carcinoma j) Carcinoma with Metaplasia a) Intraductal carcinoma b) Lobular carcinoma 3
  4. 4. Receptor Overexpression Specific for Breast Cancer Receptors Hormone receptor (HR) ER ER+ve ER-ve PR PR+ve PR-ve Tyrosine Kinase Receptor HER2 HER2+ve HER2-ve Triple negative breast cancer (TNBC) Triple-negative breast cancers are ER –ve, PR –ve and HER2-ve, hence called as triple negative breast cancer (TNBC). Less number of therapies are available for TNBC. 4
  5. 5. Globally, Breast cancer accounts for 23% of the total cancer cases and 14% of the cancer deaths in females. The cases are expected to increase by 26% by 2020 In India, premenopausal patients are about 50% of all patients. A significant proportion of Indian breast cancer patients are younger than 35 years of age. More than 80% of Indian patients are younger than 60 years of age. It constitutes >30% of all cancers in females of Delhi, Mumbai, Ahmadabad, Kolkata, and Trivandrum. 5
  6. 6. Treatments Surgery Radiotherapy Hormonal therapy Chemotherapy 6
  7. 7. Targeted Cancer Therapies Drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumor growth & progression. Most researchers consider it as new approach to treating breast cancer that targets the cell signaling pathways of cancer cells. More selective for cancer cells. Blocking of signals help to stop cancer progression and may induce cancer cell death through apoptosis. The development of targeted therapies requires the identification of good targets. 7
  8. 8. In this seminar, we are going to study breast cancer therapies which are targeted for following targets: Tyrosine Kinases Receptors Steroid Receptor Coactivators (SRC) Mammalian Target of Rapamycin (mTOR) & Phosphoinositide 3-kinase (PI3K) Poly-{adenosine diphosphate (ADP)-ribose} polymerase (PARP) 8
  9. 9. Tyrosine Kinases (TKs)  Class of enzymes which are responsible for phosphorylation of tyrosine residue on targeted proteins.  Stimulate multiple signaling pathways responsible for basic cells functions.  Several oncogenic tyrosine kinases have been detected in human malignancies. There are two families of tyrosine kinases- Transmembrane receptor kinases & Cytoplasmic non-receptor kinase a) Transmembrane kinases receptor :  Human Epidermal Receptor (HER)  Insulin like Growth Receptor (IGFR)  Fibroblast Growth Factor Receptor (FGFR)  Vascular Endothelial Growth Factor Receptor (VEGFR )  Platelet-derived Growth Factor Receptor (PDGFR) b) Cytoplasmic non-receptor kinase: Steroid Receptor Coactivators (SRC) 9
  10. 10. mTOR/PI3K/Akt Pathway IP3/DAG Pathway Ras/MAPK Pathway Multiple signaling pathways involved in the development, growth, and survival of breast cancer cells 10
  11. 11. Human Epidermal Receptors (HER) o ErbB proteins are a four-member family of highly homologous receptor tyrosine kinases comprised of ErbB1 (EGFR, HER1), ErbB2 (HER2), ErbB3 (HER3), and ErbB4 (HER4). Epidermal Growth Factor Receptor (EGFR) o It is also known as ErbB1/HER1, is essential for growth and differentiation of epithelial cells. o The expression of EGFR, ligands, and their activating proteases in breast cancers has been intensively studied. Epidermal Growth Factor Receptor Targeting Monoclonal Antibodies: Agent Class of compound Stages IMC-C225 mAb Phase II ABX-EGF mAb Phase II 11
  12. 12. Human Epidermal Receptor 2(HER2) The HER2 gene is amplified in approximately 20%-30% of breast cancers. Overexpression HER2 found in breast cancer cells which has also been associated with resistance to chemotherapy and hormone therapy. HER2 target is present in a very high proportion of tumor cells Human Epidermal Receptor 2 Targeting Monoclonal Antibodies: Agent Class of compound Stages Trastuzumab mAb Approved Trastuzumab–DM-1 mAb-toxin conjugate Approved 12
  13. 13. Trastuzumab Trastuzumab DM 1 13
  14. 14. Selected HER Family Tyrosine Kinase Inhibitors: Compound Selectivity invitro IC(Nm) Stages EGFR HER2 ZD1839, Gefitinib 27 3700 Marketed OSI-774, Erlotinib 2 350 Marketed GW572016, Lapatinib 11 9 Marketed CP-724714 4300 8 Phase II Arry-334543 7 2 Phase II CI-1033, PD183805, 0.8 19 Phase II Canertinib BIBW-2992 0.5 14 Phase II AV-412, MP-412 1 18 Phase I AEE788 6 6 Phase II EKB-569, Pelitinib 39 1200 Phase II HKI-272, Neratinib 92 59 Phase II BMS-599626 22 32 Phase I 14
  15. 15. Insulin-like Growth Factor Receptor (IGFR) IGF system is composed of IGF system Ligands IGF1 IGF2 Receptors IGF1R IGF2R Binding Proteins 6 IGFBPs ↑ circulating levels of IGF-I are associated with a greater risk of breast cancer in premenopausal women, with an especially high risk among those younger than 50 years. ↑ IGFs resists apoptosis in response to chemotherapy and radiation. IGFBPs is activated by the estrogen, which itself activates expression of IGF-15 I.
  16. 16. Insulin-like growth factor 1 receptor (IGF-1R) Targeting Agents: Agents Regimen Stages IGF-1R Antibodies CP-751,871 Docetaxel Phase II Exemestane Phase II Single agent Phase I AVE1642 / EM164 Faslodex Phase II IMC-A12 (Cixutumumab) Temsirolimus Phase I/ II Capecitabine and Lapatinib Phase II AMG 479 Exemestane or fulvestrant Phase II MK-0646/h7C10 (Dalotuzumab) Single Regimen Phase II Ridaforolimus Phase II Ridaforolimus and exemestane Phase II Dual IGF-1R–insulin receptor inhibitor BMS-754807 Trastuzumab Phase I/ II Letrozole Phase II 16
  17. 17. Fibroblast Growth Factor Receptor (FGFR) The fibroblast growth factor (FGF) consist of 18 ligands. FGF1 & FGF23 signal through four high affinity fibroblast growth factor receptor (FGFR1 to FGFR4). Under physiological conditions, the highly complex FGF signaling pathway is tightly regulated. The deregulation of FGF signaling to development of cancer, promoting cancer cell proliferation, survival and migration. 17
  18. 18. Drug class Drug name Target Stages 1st generation TKI258 (Dovitinib) FGFR, PDGFR & TKIs VEGFR Phase III BMS54021 (Brivanib) FGFR & VEGFR Phase II BIBF 1120 FGFR, PDGFR & VEGFR Phase III Ponatinib ABL, FGFR, PDGFRα, FLT3 & VEGFR2 Phase II E7080 FGFR, PDGFR, VEGFR, KIT, RET Phase I E3810 FGFR1& VEGFR1 to VEGHR3 inhibitor Phase I Sulfatinib FGFR & VEGFR inhibitor Phase I Fibroblast Growth Factor Receptor Targeting Agents: 18
  19. 19. Drug class Drug name Target Stages 2nd generation AZD 4547 Selective FGFR1, TKIs FGFR2 & FGFR3 inhibitor Phase II BGJ398 Selective pan- FGFR inhibitor Phase I FGFR antibodies IMC-A1 FGFR1-IIIc-specific antibody Preclinical GP369 FGFR2 blocking antibody Preclinical PRO-001 FGFR3-specific blocking antibody Preclinical R3Mab FGFR3-specific antibody Preclinical FGFR ligand traps FP-1039 FGF ligand traps (blocks multiple FGFs) Phase I Fibroblast Growth Factor Receptor Targeting Agents: 19
  20. 20. Vascular Endothelial Growth Factor (VEGF)  VEGF overexpression is common in breast cancer.  Bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against VEGF, was granted accelerated approval in the US for the first-line treatment of MBC in combination with Paclitaxel in 2008. 1st generation tyrosine kinase inhibitor; which also targets VEGFR are shown in previous table. Selected additional VEGF-targeted therapies:  Aflibercept or VEGF Trap is an antiangiogenic peptide-antibody fusion containing portions of human VEGF receptor 1 and 2.  Vascular disrupting agents (eg, Ombrabulin; Sanofi-Aventis) another class of antiangiogenic therapy, are under clinical trials for MBC. 20
  21. 21. Platelet Derived Growth Factor (PDGFR) PDGFR is expressed in most breast tumors. The individual PDGF chains have different affinities for the two receptors- PDGFR α & PDGFR β. PDGFR α has high affinity for PDGF -A, -B, and -C, whereas PDGFR β has high affinity for PDGF -B and –D. Induces angiogenesis by up-regulating VEGF production. 1st generation TKs; which also targets PDGFR are shown in previous table. 21
  22. 22. Steroid Receptor Coactivators (SRCs) SRCs are small proteins of 160 kDa non-receptor tyrosine kinase and include SRC-1, SRC-2/transcription intermediary factor-2 (TIF-2) and SRC-3. SRC may play a significant role in tumor progression and spread. SRC interact receptor tyrosine kinases (e.g. HER family), integrins, steroid hormone receptors, including the estrogen receptor. Steroid Receptor Coactivators (SRC) Inhibitors: Agents Stages Regimen Dasatinib Phase I/II Fulvestrant and MK-0646 Bosutinib Phase II Single Agent Saracatinib Phase II Vs Zoledronic 22
  23. 23. Mammalian Target of Rapamycin (mTOR) mTOR is a member of the cellular mTOR/PI3K/Akt pathway. A high proportion of breast tumors exhibit constitutive activation of the mTOR pathway. Rapamycin is a macrolytic lactone produced by Streptomyces hygroscopicus, which has immunosuppressive, antimicrobial, and antitumor properties. Rapamycin targets a principal protein that was named mTOR.  Two mTOR complexes have been identified: mTORC1 and mTORC2 of cell growth and proliferation, cell metabolism, angiogenesis, and apoptosis.  New agents are being developed that can inhibit both mTORC1 and mTORC2. Phosphoinositide 3-kinase (PI3K)  Three classes of PI3K enzymes, designated I to III, have been identified; members of PI3K class I have been implicated in the mTOR pathway  PI3K can be key target that, if effectively inhibited, could improve outcomes. 23
  24. 24. The mTOR/PI3K/Akt pathway PI3K inhibitor 24
  25. 25. mTOR inhibitors: Drug Drug class Stage of development Sirolimus (Rapamycin) mTOR inhibitor Approved Everolimus (RAD001) mTOR inhibitor Approved in 2012 for postmenopausal women with advanced HR+/HER2- breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole Ridaforolimus (deforolimus) (AP23573) mTOR inhibitor Phase III clinical trials PP242 mTOR inhibitor Preclinical BN107 mTOR inhibitor Preclinical 25
  26. 26. Sirolimus (Rapamycin) Everolimus 26
  27. 27. PI3K selective inhibitors: Agents Company Stage PX-866 Oncothyreon Inc Phase I GDC-0941 Genentech Inc Phase II XL-147 Exelixis Phase I/II BKM-120 Novartis Phase I 27
  28. 28. Dual kinase (mTOR &PI3K) inhibitors: Drug Drug class Stage of development PI-103 Dual kinase inhibitor Preclinical LY294002 Dual kinase inhibitor Preclinical NVP-BEZ235 Dual kinase inhibitor Phase I/II clinical trials SF1126 Dual kinase inhibitor Phase I/II XL765 Dual kinase inhibitor Phase I BGT226 Dual kinase inhibitor Phase I/II 28
  29. 29. Poly-{Adenosine diphosphate (ADP)-Ribose} Polymerase (PARP) DNA damage, double strand breaks are highly toxic to cells  Homologous recombination is DNA repair mechanism. Homologous recombination is dependent on functional BRCA 1 and 2 pathways.  Germline mutations in either the BRCA1 or BRCA2 genes are associated with a high risk of developing a number of breast cancers. When the BRCA-associated DNA repair pathway (homologous recombination) – is lost or dysfunctional, repair shifts toward alternate DNA repair mechanisms dependent on a unique class of enzymes, Poly-(adenosine diphosphate [ADP]-ribose) polymerase (PARP). 29
  30. 30. PARP-inhibitors in clinical development: Agent Company Stages Olaparib (AZD2281) AstraZeneca/KuDOS Phase I/II Veliparib Abbott Phase I/II BS1-201 BiPar/SanofiAventis Phase II/III AG014699 Pfizer Phase I/II MK482 Merck Phase I INO-1001 Inotek Phase I CEP9272 Cephalon Phase I 30
  31. 31. Conclusion Targeted cancer therapies hold the promise of being more selective, reducing side effects, and improving quality of life. Targeted therapies may work best in combination, either with other targeted therapies or with more traditional therapies. Researchers are working to find new ways to target cancer cells as part of treatment. Various targeted therapies are being studied in clinical trials to see how well they work in treating breast cancer. As more targets are identified and therapies are developed, doctors will be able to offer patients treatment that works best for their type of breast cancer. In future, metastatic breast cancer, triple negative breast cancer can be well treated. 31
  32. 32. References: 1) Harsh Mohan, Chapter 25 The Breast, Textbook of Pathology, Jaypee Brothers Medical Publishers Pvt. Ltd., 6th ed, Pg. No.754-767, 2010. 2) Bruce A. Chabner, Jeffrey Barnes, Joel Neal, Erin Olson, Hamza Mujajic, Lecia Sequist, Wynham Wilson, Dan. L. Lango, Constantine Mitsiades and Paul Richardson, Chapter 62 Targeted Therapies: Tyrosine Kinase Inhibitors, Monoclonal Antibodies and Cytokines, Goodman and Gilman’s The Pharmacological Basis of Therapeutics, Mc Graw-Hill, 12th ed, Pg. No.1731-1750, 2010. 3) Laura Boehnke Michaud and Chad M. Barnett, Chapter 136 Breast Cancer, Pharmacotherapy A Pathophysiologic Approach, Mc Graw Hill, 8th ed, Pg. No. 2229-2266, 2011. 4) Dariusz Pytel, Tomasz Sliwinski, Tomasz Poplawski, Deborah Ferriola and Ireneusz Majsterek, Tyrosine Kinase Blockers: New Hope for Successful Cancer Therapy, Anti-Cancer Agents in Medicinal Chemistry, 9th ed, Pg. No. 66-76, 2009. 5) Michelle Arkin and Mark M. Moasser, HER2 directed small molecule antagonists, Current Opinion Investigational Drugs, 9(12) Pg. No. 1264–1276, December 2008. 6) Rita Nahta, Gabriel N. Hortobagyi and Francisco J. Esteva, Growth Factor Receptors in Breast Cancer: Potential for Therapeutic Intervention, The Oncologist, 8: Pg. No. 5-17, 2003. 7) Madeleine Hewish, Ian Chau and David Cunningham, Insulin-Like Growth Factor 1 Receptor Targeted Therapeutics: Novel Compounds and Novel Treatment Strategies for Cancer Medicine, Recent Patents on Anti- Cancer Drug Discovery, 4, Pg. No. 54-72,2009. 8) Vikram K. Jain and Nicholas C. Turner, Challenges and Opportunities in The Targeting of Fibroblast Growth Factor Receptors in Breast Cancer, Breast Cancer Research, 2012, 14(3):208,http:// breast-cancer-research. com/content/14/3/208. 32
  33. 33. References: 9) Hetty Carraway and Manuel Hidalgo, New targets for therapy in breast cancer: Mammalian target of rapamycin (mTOR) antagonists, Breast Cancer Research, 6(5), Pg. No.219-224, 2004. 10) Denise A. Yardley, Combining mTOR Inhibitors with Chemotherapy and Other Targeted Therapies in Advanced Breast Cancer: Rationale, Clinical Experience, and Future Directions, Breast Cancer: Basic and Clinical Research, Pg. No. 7-22, 2013. 11) Palma Fedele, Nicola Calvani, Antonella Marino, Laura Orlando, Paola Schiavone, Annamaria Quaranta, Saverio Cinieri, Targeted Agents to Reverse Resistance to Endocrine Therapy in Metastatic Breast Cancer: Where Are We Now and Where Are We Going?, Critical Reviews in Oncology/Hematology, 84, Pg. No.243-251, 2012. 12) Carey K. Anders, Eric P. Winer, James M. Ford, Rebecca Dent, Daniel P. Silver, George W. Sledge, and Lisa A. Carey, PARP Inhibition: “Targeted” Therapy for Triple Negative Breast Cancer, Clinical Cancer Research, 16(19), Pg. No.4702-4710, October 1, 2010 . 13) Carey K. Anders, Eric P. Winer, James M. Ford, Rebecca Dent, Daniel P. Silver, George W. Sledge, and Lisa A. Carey, PARP Inhibition: “Targeted” Therapy for Triple Negative Breast Cancer, Clinical Cancer Research, 16(19), Pg. No.4702-4710, October 1, 2010. 14) M. Tenhagen, P. J. Van Diest, I. A. Ivanova, E. Van Der Wall and P. Van Der Groep, Fibroblast Growth Factor Receptors in Breast Cancer: Expression, Downstream Effects, And Possible Drug Targets, Endocrine-Related Cancer, 19, Pg. No.R115–R129, 2012. 15) Nadeem Sheikh, Saba Shehzadi and Arfa Batool, Treatment of Breast Cancer: New Approaches, Cancer Management, Pg. No.85-94 June, 2012. 16) D. Sachdev and D. Yee, The IGF system and Breast Cancer, Endocrine-Related Cancer, 8, Pg. No.197–209, 2001. 33
  34. 34. References: 17) Ahmedin Jemal, Freddie Bray, Melissa M. Center, Jacques Ferlay, Elizabeth Ward, and David Forman, Global Cancer Statistics, A Cancer Journal for Clinicians, 61(2), Pg. No. 69–90,2011. 18) Stephen Hiscox, L. Morgan, Tim Green and Robert I. Nicholson, Src as a Therapeutic Target in Antihormone Anti-growth Factor-resistant Breast Cancer, Endocrine-Related Cancer,13, Pg. No. S53–S59, 2006. 19) Dimitrios Zardavas, Jose Baselga and Martine Piccart, Emerging Targeted Agents in Metastatic Breast Cancer, Clinical Oncology, Pg. No.1-20, 2013. 20) Edith A. Perez and Jean-Philippe Spano, Current and Emerging Targeted Therapies for Metastatic Breast Cancer, Cancer, Pg. No.3014-3025, June 15, 2012. 21) Marius Raica and Anca Maria Cimpean, Platelet-Derived Growth Factor (PDGF)/PDGF Receptors (PDGFR) Axis as Target for Antitumor and Antiangiogenic Therapy Pharmaceuticals, 3, Pg. No.572-599, 2010. 22) Line L. Haugan Moi, Marianne Hauglid Flageng, Ingvild S. Fenne1, Jennifer Gjerde, Ernst A. Lien and Gunnar Mellgren, Steroid Receptor Coactivators and Their Expression, Regulation and Functional Role in Endocrine Responsive and Resistant Breast Cancer, Breast Cancer – Carcinogenesis, Cell Growth and Signaling Pathways. Pg. No.715-732, November 2011. 23) Leonel F. Hernandez-Aya, Ana M. Gonzalez-Angulo, Targeting the Phosphatidylinositol 3-Kinase Signaling Pathway in Breast Cancer, The Oncologist, 16, Pg. No.404–414, 2011. 34
  35. 35. Thank You 35

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