Evaluation of ERα, PR and ERβ isoforms in neoadjuvant treated breast cancer

The actual predictive value of oestrogen receptor (ER) beta for treatment decisions in breast cancer is still unclear. Retrospective studies using preoperative systemic therapy (PST) revealed that chemotherapy but also endocrine therapy can lead to alterations in expression levels of ERalpha and progesterone receptor (PR). The main purpose of this study was to compare ERbeta expression levels before and after neoadjuvant chemotherapy or endocrine therapy and to explore a possible predictive value of ERbeta. Matching 'baseline' biopsies and post-therapy surgical specimens of 69 breast cancer patients treated with neoadjuvant anthracycline- or taxane-based chemotherapy or with aromatase inhibitors were analyzed for expression levels of ERalpha, PR, total ERbeta (ERbetat), ERbeta1, ERbeta2 and the proliferation-related antigen Ki-67 using immunohistochemistry. A marked expression of ERbetat significantly correlates with low proliferation rates after PST (p=0.0013) and with response to it. Further most tumours decreased ERbeta1 expression with PST. A marked ERbeta2 expression was observed predominantly in responders and significantly decreased during chemotherapy (p=0.047). Results on ERalpha and PR corroborate findings of previous studies. Our data demonstrate that changes of ERbeta expression occur during PST and that total ERbeta expression and ERbeta2 may have a predictive value for PST.

[1]  N. Harada,et al.  Oestrogen receptor‐β1 but not oestrogen receptor‐βcx is of prognostic value in apocrine carcinoma of the breast   , 2008, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[2]  T. Fehm,et al.  ERalpha-status of disseminated tumour cells in bone marrow of primary breast cancer patients , 2008, Breast Cancer Research.

[3]  I. Ellis,et al.  Nuclear and Cytoplasmic Expression of ERβ1, ERβ2, and ERβ5 Identifies Distinct Prognostic Outcome for Breast Cancer Patients , 2008, Clinical Cancer Research.

[4]  T. Fehm,et al.  Changes in tumour biological markers during primary systemic chemotherapy (PST). , 2008, Anticancer research.

[5]  K. Hess,et al.  Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. , 2008, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[6]  F. Xie,et al.  Biological markers as predictive factors of response to neoadjuvant taxanes and anthracycline chemotherapy in breast carcinoma. , 2008, Chinese medical journal.

[7]  L. Murphy,et al.  Estrogen receptor alpha negative breast cancer patients: Estrogen receptor beta as a therapeutic target , 2008, The Journal of Steroid Biochemistry and Molecular Biology.

[8]  K. Dahlman-Wright,et al.  Estrogen Receptor β: An Overview and Update , 2008 .

[9]  Kenneth M. Yamada,et al.  Cell–matrix adhesion , 2007, Journal of cellular physiology.

[10]  T. Toyama,et al.  Expression of Estrogen Receptor β Wild-type and its Variant ERβcx/β2 is Correlated with Better Prognosis in Breast Cancer , 2007 .

[11]  O. Ortmann,et al.  Novel estrogen receptor beta transcript variants identified in human breast cancer cells affect cell growth and apoptosis of COS-1 cells , 2007, Molecular and Cellular Endocrinology.

[12]  W. Miller,et al.  Oestrogen receptor β and neoadjuvant therapy with tamoxifen: prediction of response and effects of treatment , 2006, British Journal of Cancer.

[13]  T. Karn,et al.  Gene Expression Profiles of Breast Cancer Obtained from Core Cut Biopsies Before Neoadjuvant Docetaxel, Adriamycin, and Cyclophoshamide Chemotherapy Correlate with Routine Prognostic Markers and Could Be Used to Identify Predictive Signatures , 2005, Zentralblatt fur Gynakologie.

[14]  W. Miller,et al.  Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole , 2006, British Journal of Cancer.

[15]  M. Bissell,et al.  Of extracellular matrix, scaffolds, and signaling: tissue architecture regulates development, homeostasis, and cancer. , 2006, Annual review of cell and developmental biology.

[16]  D. Harrison,et al.  ERβ isoform expression in colorectal carcinoma: an in vivo and in vitro study of clinicopathological and molecular correlates , 2005, The Journal of pathology.

[17]  J. Gustafsson,et al.  Increased Estrogen Receptor βcx Expression during Mammary Carcinogenesis , 2005, Clinical Cancer Research.

[18]  M. Dowsett,et al.  Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: influence of hormonal status and HER-2 in breast cancer--a study from the IMPACT trialists. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  A. Makris,et al.  Evaluation of ER, PgR, HER-2 and Ki-67 as predictors of response to neoadjuvant anthracycline chemotherapy for operable breast cancer , 2004, British Journal of Cancer.

[20]  S. Angeloni,et al.  Regulation of estrogen receptor-alpha expression in MCF-7 cells by taxol. , 2004, The Journal of endocrinology.

[21]  Y. Omoto,et al.  Estrogen receptor (ER) β1 and ERβcx/β2 inhibit ERα function differently in breast cancer cell line MCF7 , 2003, Oncogene.

[22]  D. Cameron,et al.  Pathological features of breast cancer response following neoadjuvant treatment with either letrozole or tamoxifen. , 2003, European journal of cancer.

[23]  M. Gnant,et al.  Sequential steroid hormone receptor measurements in primary breast cancer with and without intervening primary chemotherapy. , 2003, Endocrine-related cancer.

[24]  P. Saunders,et al.  Wild-type estrogen receptor (ERbeta1) and the splice variant (ERbetacx/beta2) are both expressed within the human endometrium throughout the normal menstrual cycle. , 2002, The Journal of clinical endocrinology and metabolism.

[25]  Katarzyna Kalita,et al.  Estrogen receptor β , 2002 .

[26]  J. Dixon,et al.  Effect of neoadjuvant treatment with anastrozole on tumour histology in postmenopausal women with large operable breast cancer , 2002, British Journal of Cancer.

[27]  C. Clarke,et al.  Detection of progesterone receptor forms A and B by immunohistochemical analysis , 2001, Journal of clinical pathology.

[28]  V. Speirs,et al.  Immunohistochemical detection of ERβ in breast cancer: towards more detailed receptor profiling? , 2001, British Journal of Cancer.

[29]  Richard A. Anderson,et al.  Differential Expression of Estrogen Receptor-α and -β and Androgen Receptor in the Ovaries of Marmosets and Humans , 2000 .

[30]  D Barnes,et al.  Immunohistochemical detection of steroid receptors in breast cancer: a working protocol , 2000, Journal of clinical pathology.

[31]  P. Hilton,et al.  Oestrogen and progesterone receptor expression in the female lower urinary tract, with reference to oestrogen status , 2000, BJU international.

[32]  Johannes Gerdes,et al.  The Ki‐67 protein: From the known and the unknown , 2000, Journal of cellular physiology.

[33]  C. Stein Mechanisms of action of taxanes in prostate cancer. , 1999, Seminars in oncology.

[34]  Y. Ouchi,et al.  Molecular cloning and characterization of human estrogen receptor βcx: A potential inhibitor of estrogen action in human , 1998 .

[35]  J. Lehmann,et al.  Cloning and Characterization of Human Estrogen Receptor β Isoforms , 1998 .

[36]  F. Fitzpatrick,et al.  Taxane-mediated gene induction is independent of microtubule stabilization: induction of transcription regulators and enzymes that modulate inflammation and apoptosis. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[37]  F. Adami,et al.  Changes of biological features in breast cancer cells determined by primary chemotherapy , 1997, Breast Cancer Research and Treatment.

[38]  Johannes Gerdes,et al.  Monoclonal antibodies against recombinant parts of the Ki‐67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave‐processed formalin‐fixed paraffin sections , 1992, The Journal of pathology.

[39]  J. Gerdes,et al.  Immunohistological detection of tumour growth fraction (Ki-67 antigen) in formalin-fixed and routinely processed tissues. , 1992, The Journal of pathology.

[40]  J. Bartek,et al.  Novel monoclonal antibodies defining epitope of human cytokeratin 18 molecule. , 1988, Hybridoma.

[41]  W. Remmele,et al.  [Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue]. , 1987, Der Pathologe.

[42]  P. Schiff,et al.  Taxol stabilizes microtubules in mouse fibroblast cells. , 1980, Proceedings of the National Academy of Sciences of the United States of America.

[43]  P. Liu,et al.  Response to neoadjuvant therapy and disease free survival in patients with triple-negative breast cancer. , 2009, Gan to kagaku ryoho. Cancer & chemotherapy.

[44]  T. Fehm,et al.  A laminin-rich basement membrane matrix influences estrogen receptor beta expression and morphology of MDA-MB-231 breast cancer cells. , 2009, Oncology reports.

[45]  N. Tanić,et al.  Expression of estrogen receptor beta wt isoform (ERbeta1) and ERbetaDelta5 splice variant mRNAs in sporadic breast cancer. , 2007, Journal of cancer research and clinical oncology.

[46]  Micah Dembo,et al.  Mammary epithelial cell: influence of extracellular matrix composition and organization during development and tumorigenesis. , 2007, The international journal of biochemistry & cell biology.

[47]  S. Ho,et al.  Estrogen receptor (ER)-beta isoforms: a key to understanding ER-beta signaling. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[48]  M J Bissell,et al.  Microenvironmental Regulators of Tissue Structure and Function Also Regulate Tumor Induction and Progression : The Role of Extracellular Matrix and Its Degrading Enzymes , 2022 .

[49]  D. Mitter,et al.  [Estrogen receptor Beta isoforms -- functions and clinical relevance in breast cancer]. , 2005, Zentralblatt fur Gynakologie.

[50]  V. Speirs,et al.  Oestrogen receptor beta: what it means for patients with breast cancer. , 2004, The Lancet. Oncology.

[51]  C. Foster Evaluation of seven oestrogen receptor beta antibodies for immunohistochemistry, western blotting, and flow cytometry in human breast tissue , 2003 .

[52]  V. Speirs,et al.  Distinct expression patterns of ER alpha and ER beta in normal human mammary gland. , 2002, Journal of clinical pathology.

[53]  Jessy Abraham,et al.  Identification of ten exon deleted ERbeta mRNAs in human ovary, breast, uterus and bone tissues: alternate splicing pattern of estrogen receptor beta mRNA is distinct from that of estrogen receptor alpha. , 2002, FEBS letters.

[54]  R. Sharpe,et al.  ERbeta1 and the ERbeta2 splice variant (ERbetacx/beta2) are expressed in distinct cell populations in the adult human testis. , 2002, The Journal of clinical endocrinology and metabolism.

[55]  A. Lucas,et al.  ER beta inhibits proliferation and invasion of breast cancer cells. , 2001, Endocrinology.

[56]  Longgui Wang,et al.  The effect of antimicrotubule agents on signal transduction pathways of apoptosis: a review , 1999, Cancer Chemotherapy and Pharmacology.

[57]  H. Junkermann,et al.  [Histologic regression of breast cancer after primary (neoadjuvant) chemotherapy]. , 1994, Geburtshilfe und Frauenheilkunde.