Endocrine-resistant breast cancer: Underlying mechanisms and strategies for overcoming resistance

Estrogen plays important roles in the development and progression of breast cancer. However, onethird of breast cancers fail to respond to endocrine therapy and most endocrine-responsive breast cancers subsequently become resistant to endocrine therapy. A tremendous effort has been made to elucidate the mechanisms responsible for the development of endocrine-resistance in breast cancer. Since the main target molecule of estrogen in breast cancer is estrogen receptor (ER)-α, most studies have focused on investigating quantitative and qualitative changes in ER-α in endocrine-resistant breast cancer. Breast cancers expressing no ER-α fail to respond to endocrine therapy. Some breast cancers expressing ER-α also fail to respond to endocrine therapy and most breast cancers with acquired endocrine resistance retain ER-α expression, which suggests that the disappearance of ER-α in breast cancer cells is not a common cause of resistance to endocrine therapy. Recent molecular biological studies have shown evidence that qualitative and functional changes, such as gene mutations and phosphorylation of ER-α, cause endocrine resistance in breast cancer. In addition, it has been suggested that endocrine resistance could be induced by epigenetic changes, such as hypoxia, in breast cancer tissues. Understanding the precise mechanisms that underlie endocrine resistance may enable clinicians to develop new strategies for retarding or overcoming endocrine resistance in breast cancer.

[1]  H. Kurokawa,et al.  Inhibition of erbB receptor (HER) tyrosine kinases as a strategy to abrogate antiestrogen resistance in human breast cancer. , 2001, Clinical cancer research : an official journal of the American Association for Cancer Research.

[2]  D B Evans,et al.  Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  A. Harris,et al.  Prognostic significance of a novel hypoxia-regulated marker, carbonic anhydrase IX, in invasive breast carcinoma. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[4]  K. Horwitz,et al.  Nuclear receptor conformation, coregulators, and tamoxifen-resistant breast cancer , 2000, Steroids.

[5]  M. Dowsett,et al.  Exon 5 deletion variant estrogen receptor messenger RNA expression in relation to tamoxifen resistance and progesterone receptor/pS2 status in human breast cancer. , 1995, Cancer research.

[6]  S. Kato,et al.  A novel isoform of rat estrogen receptor beta with 18 amino acid insertion in the ligand binding domain as a putative dominant negative regular of estrogen action. , 1998, Biochemical and biophysical research communications.

[7]  A. Bitonti,et al.  Progression of MCF-7 breast cancer cells to antiestrogen-resistant phenotype is accompanied by elevated levels of AP-1 DNA-binding activity. , 1996, Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research.

[8]  N. Rosen,et al.  The tyrosine kinase inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and suppresses the growth of HER2-overexpressing tumor cells. , 2001, Cancer research.

[9]  B. Katzenellenbogen,et al.  A role for Akt in mediating the estrogenic functions of epidermal growth factor and insulin-like growth factor I. , 2000, Endocrinology.

[10]  M. Fernö,et al.  ErbB2 status and the benefit from two or five years of adjuvant tamoxifen in postmenopausal early stage breast cancer. , 2000, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  Daniel Metzger,et al.  Activation of the Estrogen Receptor Through Phosphorylation by Mitogen-Activated Protein Kinase , 1995, Science.

[12]  J. Farndon,et al.  EPIDERMAL-GROWTH-FACTOR RECEPTOR STATUS AS PREDICTOR OF EARLY RECURRENCE OF AND DEATH FROM BREAST CANCER , 1987, The Lancet.

[13]  J. Blenis,et al.  pp90rsk1 Regulates Estrogen Receptor-Mediated Transcription through Phosphorylation of Ser-167 , 1998, Molecular and Cellular Biology.

[14]  Simak Ali,et al.  Activation of estrogen receptor alpha by S118 phosphorylation involves a ligand-dependent interaction with TFIIH and participation of CDK7. , 2000, Molecular cell.

[15]  D. Slamon,et al.  Rationale for trastuzumab (Herceptin) in adjuvant breast cancer trials. , 2001, Seminars in oncology.

[16]  R. Coombes,et al.  Estrogen receptors and proliferation markers in primary and recurrent breast cancer , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Simak Ali,et al.  Phosphorylation of Human Estrogen Receptor α by Protein Kinase A Regulates Dimerization , 1999, Molecular and Cellular Biology.

[18]  J. Foekens,et al.  Ectopic expression of epidermal growth factor receptors induces hormone independence in ZR-75-1 human breast cancer cells. , 1992, Cancer research.

[19]  R. Bianco,et al.  Epidermal growth factor receptor (HER1) tyrosine kinase inhibitor ZD1839 (Iressa) inhibits HER2/neu (erbB2)-overexpressing breast cancer cells in vitro and in vivo. , 2001, Cancer research.

[20]  K. Horwitz,et al.  The partial agonist activity of antagonist-occupied steroid receptors is controlled by a novel hinge domain-binding coactivator L7/SPA and the corepressors N-CoR or SMRT. , 1997, Molecular endocrinology.

[21]  J. Kurebayashi,et al.  Current status and controversial issues concerning endocrine therapy for patients with recurrent breast cancer in Japan , 1999, Breast cancer.

[22]  V. Speirs,et al.  Expression of alternatively spliced estrogen receptor alpha mRNAs is increased in breast cancer tissues , 2001, The Journal of Steroid Biochemistry and Molecular Biology.

[23]  K.,et al.  Diverse signaling pathways modulate nuclear receptor recruitment of N-CoR and SMRT complexes. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[24]  M. Dowsett,et al.  Increased activator protein-1 DNA binding and c-Jun NH2-terminal kinase activity in human breast tumors with acquired tamoxifen resistance. , 1999, Clinical cancer research : an official journal of the American Association for Cancer Research.

[25]  M. Sliwkowski,et al.  HER-2 tyrosine kinase pathway targets estrogen receptor and promotes hormone-independent growth in human breast cancer cells. , 1995, Oncogene.

[26]  I. Ellis,et al.  Epidermal growth factor receptor expression in breast cancer: Association with response to endocrine therapy , 2004, Breast Cancer Research and Treatment.

[27]  P. Band,et al.  Tamoxifen-induced tumor stimulation and withdrawal response. , 1979, Cancer treatment reports.

[28]  Y. Higashi,et al.  Distinct mechanisms of loss of estrogen receptor alpha gene expression in human breast cancer: methylation of the gene and alteration of trans-acting factors. , 2000, Carcinogenesis.

[29]  M. Mesiti,et al.  Sequential tamoxifen and aminoglutethimide versus tamoxifen alone in the adjuvant treatment of postmenopausal breast cancer patients: results of an Italian cooperative study. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[30]  B. Leyland-Jones.  Trastuzumab: hopes and realities. , 2002, The Lancet. Oncology.

[31]  B. Katzenellenbogen,et al.  Constitutively active human estrogen receptors containing amino acid substitutions for tyrosine 537 in the receptor protein. , 1996, Molecular endocrinology.

[32]  Simak Ali,et al.  Phosphatidylinositol 3-Kinase/AKT-mediated Activation of Estrogen Receptor α , 2001, The Journal of Biological Chemistry.

[33]  A. Howell,et al.  Response after withdrawal of tamoxifen and progestogens in advanced breast cancer. , 1992, Annals of oncology : official journal of the European Society for Medical Oncology.

[34]  C. Osborne,et al.  Mechanisms for tamoxifen resistance in breast cancer: Possible role of tamoxifen metabolism , 1993, The Journal of Steroid Biochemistry and Molecular Biology.

[35]  S. Inoue,et al.  Evaluation of oestrogen receptor beta wild-type and variant protein expression, and relationship with clinicopathological factors in breast cancers. , 2002, European journal of cancer.

[36]  D. Dearnaley,et al.  A pilot study of intermittent androgen deprivation in advanced prostate cancer. , 1998, British journal of urology.

[37]  P. Vaupel,et al.  Tumor hypoxia: definitions and current clinical, biologic, and molecular aspects. , 2001, Journal of the National Cancer Institute.

[38]  R. Laucirica,et al.  Estrogen receptor beta expression in invasive breast cancer. , 2001, Human pathology.

[39]  D. Picard,et al.  Activation of the unliganded estrogen receptor by EGF involves the MAP kinase pathway and direct phosphorylation. , 1996, The EMBO journal.

[40]  D. Gandara,et al.  Tirapazamine: prototype for a novel class of therapeutic agents targeting tumor hypoxia. , 2002, Seminars in oncology.

[41]  H. Doihara,et al.  Anti-HER2 antibody enhances the growth inhibitory effect of anti-oestrogen on breast cancer cells expressing both oestrogen receptors and HER2 , 1999, British Journal of Cancer.

[42]  P. Bunn,et al.  ZD1839, a selective epidermal growth factor receptor tyrosine kinase inhibitor, alone and in combination with radiation and chemotherapy as a new therapeutic strategy in non-small cell lung cancer. , 2002, Seminars in oncology.

[43]  N. Roodi,et al.  Estrogen receptor gene analysis in estrogen receptor-positive and receptor-negative primary breast cancer. , 1995, Journal of the National Cancer Institute.

[44]  J. Klijn,et al.  Combined treatment with buserelin and tamoxifen in premenopausal metastatic breast cancer: a randomized study. , 2000, Journal of the National Cancer Institute.

[45]  L. Murphy,et al.  Prevalence of estrogen receptor variant messenger RNAs in human breast cancer. , 1996, Cancer research.

[46]  B. Katzenellenbogen,et al.  Estrogen receptor activation function 1 works by binding p160 coactivator proteins. , 1998, Molecular endocrinology.

[47]  I. Ellis,et al.  Phosphorylation of ERK1/2 mitogen‐activated protein kinase is associated with poor response to anti‐hormonal therapy and decreased patient survival in clinical breast cancer , 2001, International journal of cancer.

[48]  M. Wigler,et al.  PTEN, a Putative Protein Tyrosine Phosphatase Gene Mutated in Human Brain, Breast, and Prostate Cancer , 1997, Science.

[49]  A. Hart,et al.  Differences in estrogen receptor alpha variant messenger RNAs between normal human breast tissue and primary breast carcinomas. , 2000, Cancer research.

[50]  R. Roeder,et al.  HATs off: selective synthetic inhibitors of the histone acetyltransferases p300 and PCAF. , 2000, Molecular cell.

[51]  V. Jordan,et al.  Development of tamoxifen-stimulated growth of MCF-7 tumors in athymic mice after long-term antiestrogen administration. , 1988, Cancer research.

[52]  Point mutation of estrogen receptor (ER) in the ligand-binding domain changes the pharmacology of antiestrogens in ER-negative breast cancer cells stably expressing complementary DNAs for ER. , 1992, Molecular endocrinology.

[53]  S. Hilsenbeck,et al.  Oxidative stress and AP-1 activity in tamoxifen-resistant breast tumors in vivo. , 2000, Journal of the National Cancer Institute.

[54]  P. Ravdin,et al.  Endocrine status of premenopausal node-positive breast cancer patients following adjuvant chemotherapy and long-term tamoxifen. , 1988, Cancer research.

[55]  E. Kalkhoven,et al.  Ligand‐independent activation of the oestrogen receptor by mutation of a conserved tyrosine , 1997, The EMBO journal.

[56]  D. Miles,et al.  Overexpression of c-erbB2 is an independent marker of resistance to endocrine therapy in advanced breast cancer , 1999, British Journal of Cancer.

[57]  J. Kurebayashi,et al.  Hypoxia Reduces Hormone Responsiveness of Human Breast Cancer Cells , 2001, Japanese journal of cancer research : Gann.