title: Significance of ER-Src axis in hormonal therapy resistance.
abstract: The estrogen receptor (ER) is implicated in the progression of breast cancer. Despite positive effects of hormonal therapy, initial or acquired resistance to endocrine therapies frequently occurs. Recent studies suggested ERα-coregulator PELP1 and growth factor receptor ErbB2/HER2 play an essential role in hormonal therapy responsiveness. Src axis couples ERα with HER2 and PELP1, thus representing a new pathway for targeted therapy resistance. To establish the significance of ER-Src axis in PELP1 and HER2 mediated therapy resistance, we have generated model cells that stably express Src-shRNA under conditions of PELP1, HER2 deregulation. Depletion of Src using shRNA substantially reduced E2 mediated activation of Src and MAPK activation in resistant model cells. Pharmacological inhibition of Src using dasatinib, an orally available inhibitor substantially inhibited the growth of therapy resistant MCF7-PELP1, MCF7-HER2, and MCF7-Tam model cells in proliferation assays. In post-menopausal xenograft based studies, treatment with dasatinib significantly inhibited the growth of therapy resistant cells. IHC analysis revealed that the tumors were ERα positive, and dasatinib treated tumors exhibited alterations in Src and MAPK signaling pathways. Combinatorial therapy of tamoxifen with dasatinib showed better therapeutic effect compared to single agent therapy on the growth of therapy resistant PELP1 driven tumors. The results from our study showed that ER-Src axis play an important role in promoting hormonal resistance by proto-oncogenes such as HER2, PELP1, and blocking this axis prevents the development of hormonal independence in vivo. Since PELP1, HER2, and Src kinase are commonly deregulated in breast cancers, combination therapies using both endocrine agents and dasatinib may have better therapeutic effect by delaying the development of hormonal resistance.
authors.affiliation: Department of Obstetrics and Gynecology and CTRC, The UT Health Science Center at San Antonio, 7703 Floyd Curl Drive, Mail Code 7836, San Antonio, TX 78229-3900, USA.
authors.forename: Sreeram
authors.initials: S
authors.lastname: Vallabhaneni
authors.forename: Binoj C
authors.initials: BC
authors.lastname: Nair
authors.forename: Valerie
authors.initials: V
authors.lastname: Cortez
authors.forename: Rambabu
authors.initials: R
authors.lastname: Challa
authors.forename: Dimple
authors.initials: D
authors.lastname: Chakravarty
authors.forename: Rajeshwar Rao
authors.initials: RR
authors.lastname: Tekmal
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D056970:Co-Repressor Proteins / Q000235:genetics / Q000378:metabolism; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D004357:Drug Synergism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology / Q000627:therapeutic use; D010766:Phosphorylation; D011743:Pyrimidines / Q000494:pharmacology* / Q000627:therapeutic use; D034622:RNA Interference; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D013629:Tamoxifen / Q000494:pharmacology / Q000627:therapeutic use; D013844:Thiazoles / Q000494:pharmacology* / Q000627:therapeutic use; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D056970:Co-Repressor Proteins; D000069439:Dasatinib; D047628:Estrogen Receptor alpha; D000077289:Letrozole; D020928:Mitogen-Activated Protein Kinases; D009570:Nitriles; D011743:Pyrimidines; D018719:Erb-b2 Receptor Tyrosine Kinases; D013629:Tamoxifen; D013844:Thiazoles; D014157:Transcription Factors; D014230:Triazoles; D019061:src-Family Kinases; C506487:ESR1 protein, human; C438485:PELP1 protein, human; C508053:ERBB2 protein, human