Citation of original article:

R. Narayanan, D. P. Edwards, N. L. Weigel. Human progesterone receptor displays cell cycle-dependent changes in transcriptional activity. Molecular and Cellular Biology 2005; 25(8): 2885–2898.

Abstract of the original article

The human progesterone receptor (PR) contains multiple Ser-Pro phosphorylation sites that are potential substrates for cyclin-dependent kinases, suggesting that PR activity might be regulated during the cell cycle. Using T47D breast cancer cells stably transfected with an mouse mammary tumor virus (MMTV) chloramphenicol acetyltransferase reporter (Cat0) synchronized in different phases of the cell cycle, we found that PR function and phosphorylation is remarkably cell cycle dependent, with the highest activity in S phase. Although PR expression was reduced in the G2/M phase, the activity per molecule of receptor was markedly reduced in both G1 and G2/M phases compared to the results seen with the S phase of the cell cycle. Although PR is recruited to the MMTV promoter equivalently in the G1 and S phases, recruitment of SRC-1, SRC-3, and, consequently, CBP is reduced in G1 phase despite comparable expression levels of SRC-1 and SRC-3. In G2/M phase, site-specific phosphorylation of PR at Ser162 and at Ser294, a site previously reported to be critical for transcriptional activity and receptor turnover, was abolished. Treatment with the histone deacetylase inhibitor trichostatin A elevated G1 and G2/M activity to that of the S phase, indicating that the failure to recruit sufficient levels of active histone acetyltransferase is the primary defect in PR-mediated transactivation.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by American College of Surgeons Oncology Group (ACOSOG). Clinical trials include:

1. ACOSOG Z1031: A randomized phase III trial comparing 16–18 weeks of neoadjuvant exemestane (25mg daily), letrozole (2.5mg), or anastrozole (1mg) in postmenopausal women with clinical stages II and III estrogen receptor positive breast cancer.

2. ACOSOG Z0010: A prognostic study of sentinel node and bone marrow micrometastases in women with clinical T1 or T2 N0 M0 breast cancer.

3. ACOSOG Z0011: A randomized trial of axillary node dissection in women with clinical T1–2 N0 M0 breast cancer who have a positive sentinel node.

This section provides current contact details and a list of recent or ongoing clinical trials that the Australian New Zealand Breast Cancer Trials Group(ANZ BCTG) participate in with other clinical trials groups, if applicable.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Adjuvant tamoxifen – longer against shorter (ATLAS). Clinical trials include:

1. Phase III ATLAS adjuvant tamoxifen – longer against shorter: an international trial of adjuvant hormonal treatment duration (www.ctsu.ox.ac.uk/~atlas/index.html).

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Dutch breast cancer trialists' group (BOOG). Clinical trials include:

1. An open label randomized (inter)national multicenter comparative trial of 5 years adjuvant endocrine therapy with an LHRH agonist plus an aromatase inhibitor (goserelin + anastrozole) versus five courses FE90C chemotherapy followed by the same endocrine therapy in pre- or perimenopausal patients with hormone receptor-positive primary breast cancer (PRemenopausal Optimal Management IS Endocrine therapy). BOOG 2002-01/PROMISE. ISRCTN23561723

2. Open label, comparative, randomized, multicenter, study of trastuzumab (Herceptin) given with docetaxel (Taxotere) versus sequential single agent therapy with trastuzumab followed by docetaxel as first-line treatment for metastatic breast cancer (MBC) patients with HER2neu overexpression. BOOG 2002-02/HERTAX ISRCTN13770586

3. Micro-metastases and Isolated tumour cells: Robust and Relevant Or Rubbish? The MIRROR study in BREAST CANCER. BOOG 2003-03/ZonMW 3214

4. Radiation dose intensity study in breast cancer in young women: a randomized phase III trial of additional dose to the tumor bed. BOOG 2004-01/Young Boost SRCTN45066831

5. Microarray analysis in breast cancer to Tailor Adjuvant Drugs Or Regimens, a randomized phase III study. MATADOR, BOOG 2005-02, CKTO 2004-04 ISRCTN61893718

6. A prospective randomised, open, multicentre, phase III study to assess different Durations of Anastrozole therapy after 2–3 years Tamoxifen as Adjuvant therapy in postmenopausal women with breast cancer. 2006-01/DATA

7. A randomized, open-label phase III study of first line chemotherapy in elderly metastatic breast cancer patients, comparing intravenous pegylated liposomal doxorubicin with oral capecitabine; and the incorporation of a complete geriatric assessment. 2006-02/OMEGA

8. BOOG participation in International studies:. BOOG 2001-01/TEAM trial. BOOG 2001-02/AMAROS (EORTC 10981/22023). BOOG 2002-04/HERA (BIG 1-01/EORTC 10011/BO16348B). BOOG 2003-02 (BIG 1-02/IBCSG 27-02). BOOG 2003-04 (GBG 29). BOOG 2004-02/TBP (GBG 26, BIG 3-05). BOOG 2005-01/CASA (IBCSG 32-05/BIG 1-05). BOOG 2005-03/MINDACT (EORTC 10041, BIG 3-04). BOOG 2006-03/SUPREMO (BIG 2-04). BOOG 2006-04/Adjuvant lapatinib study (BIG 2-06/EGF106708)

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Breast European Adjuvant Studies Team (BREAST). Clinical trials include:

1. An intergroup phase III trial to evaluate the activity of docetaxel, given either sequentially or in combination with doxorubicin, followed by CMF, in comparison to doxorubicin alone or in combination with cyclophos-phamide, followed by CMF, in the adjuvant treatment of node-positive breast cancer patients. BIG 02-98/TAX 315

2. HERA: A randomized three-arm multi-centre comparison of 1 year and 2 years of Herceptin versus no Herceptin in women with HER2-positive primary breast cancer who have completed adjuvant chemotherapy. BIG 01-01/B016348

3. Adjuvant trial with lapatinib and trastuzumab* (BIG) *trial title/acronym not available at time of publication.

This section provides current contact details and a list of recent or ongoing clinical trials that the Central and East European Oncology Group (CEEOG) participate in with other clinical trials groups, if applicable.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Cancer International Research Group (CIRG). Clinical trials include:

1. A multicenter phase III randomized trial comparing docetaxel in combination with doxorubicin and cyclophosphamide (TAC) versus doxorubicin and cyclophosphamide followed by docetaxel (A → CT) as adjuvant treatment of operable breast cancer her2neu-negative patients with positive axillary lymph nodes.CIRG 005

2. Multicenter phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel (AC→T) with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab (AC→TH) and with docetaxel, carboplatin and trastuzumab (TCH) in the adjuvant treatment of node-positive and high-risk node-negative patients with operable breast cancer containing the her2neu alteration. BCIRG 006.

3. A multicenter phase III randomized trial comparing docetaxel (Taxotere) and trastuzumab (Herceptin) with docetaxel (Taxotere), platinum salt (cisplatin or carboplatin) and trastuzumab (Herceptin) as first line chemotherapy for patients with advanced breast cancer containing the her2neu alteration. BCIRG 007

This section provides current contact details and a list of recent or ongoing clinical trials that the Danish Breast Cancer Cooperative Group (DBCG) participate in with other clinical trials groups, if applicable.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Fondazione Michelangelo Breast Cancer Group (FM-B). Clinical trials include:

1. European cooperative study of chemotherapy and surgery comparing adjuvant doxorubicin followed by CMF versus adjuvant doxorubicin/paclitaxel followed by CMF versus primary doxorubicin/paclitaxel followed by CMF in women with operable breast cancer and T > 2cm.

2. European Cooperative Study of Primary Systemic Therapy in Women with Operable Breast Cancer and T > 2cm.

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by European Organization for Research and Treatment of Cancer – Breast Cancer Group (EORTC BCG). Clinical trials include:

1. Postoperative adjuvant chemotherapy followed by adjuvant tamoxifen versus nil for node-negative and node-positive patients with operable breast cancer. EORTC Study No. 10901

2. Randomized phase III study comparing short, intensive preoperative combination chemotherapy with similar therapy given postoperatively. EORTC Trial No. 10902

3. Phase III randomized trial investigating the role of internal mammary and medial supraclavicular (IM-MS) lymph node chain irradiation in stage I–III breast cancer (joint study of the EORTC Radiotherapy Cooperative Group and the EORTC Breast Cancer Cooperative Group). EORTC Study No. 10925/22922

4. A survey of the Breast International Group (BIG) to assess the attitude of patients aged <35 years, with early breast cancer, toward the risk of loss of fertility related to adjuvant therapies. BIG 3-98/EORTC 10002

5. LAMANOMA: Conservative local treatment versus mastectomy after induction chemotherapy in locally advanced breast cancer: a randomized phase III study. BIG 2-00/EORTC Study No. 10974/22002

6. p53 study: First prospective intergroup translational research trial assessing the potential predictive value of p53 using a functional assay in yeast in patients with locally advanced/inflammatory or large operable breast cancer, prospectively randomized to a taxane versus non-taxane regimen. BIG 1-00/EORTC 10994

7. After mapping of the axilla: radiotherapy or surgery AMAROS. EORTC 10981/22023

8. A randomized phase II–III trial evaluating the efficacy of capecitabine and vinorelbine in anthracycline and taxane pretreated metastatic breast cancer. EORTC 10001/160010

9. Phase I study of lonafarnib (SCH 66336) in combination with Herceptin plus paclitaxel in HER-2 neu overexpressing breast cancer. EORTC 10051/16023

10. MINDACT trial: A prospective, randomized study comparing the Amsterdam 70-gene expression signature (Mammaprint) with common clinical pathological criteria in selecting patients for adjuvant chemotherapy in node-negative breast cancer. BIG 3-04/EORTC 10041

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by Finnish Breast Cancer Group (FBCG). Clinical trials include:

1. Comparison of vinorelbine versus docetaxel, and trastuzumab versus no trastuzumab as adjuvant treatments of early breast cancer. FinHer study

2. Randomized phase III study comparing single-agent docetaxel followed by 5-FU, epirubicin and cyclophosphamide (FEC) to docetaxel plus Xeloda followed by cyclophosphamide, epirubicin and Xeloda (CEX) as adjuvant treatment for early breast cancer. FinXX Study

3. A multicenter phase III open randomised trial of the efficacy of exercise in the prevention of long-term adverse effects of adjuvant treatments and breast cancer recurrences in women with primary breast cancer. BREX 01-2004 Study

This section provides current contact details and a summary of recent or ongoing clinical trials being coordinated by German Breast Group (GBG). Clinical trials include:

1. A multi-center randomized Phase III study evaluating 4 cycles of docetaxel, doxorubicin and cyclophosphamide (TAC) versus 4 cycles of vinorelbine and capecitabine (NX) in patients not sufficiently responding to 2 cycles of TAC and 4 cycles of TAC versus 6 cycles of TAC in patients sufficiently responding to 2 cycles of TAC as preoperative treatment of locally advanced (T4 a-d, N0-3,M0) or operable (T ≥ 2 cm, N0-2,M0) primary breast cancer/GBG 24.

2. A multi-center randomized Phase III study to compare capecitabine alone or in combination with trastuzumab in patients with HER-2 positive metastatic breast cancer and progression after previous treatment with trastuzumab (Treatment Beyond Progression, TBP). BIG 3-05-GBG26

3. A Phase III multi-centre double blind randomized trial of celecoxib versus placebo in primary breast cancer patients. BIG 1-03-ICCG/C/20/01 - GBG27 (see also description under ICCG)

4. Prospective Register Study of the German Adjuvant Breast Cancer Study Group (GABG) or Diagnosis and Treatment of Breast Cancer in Pregnancy / BIG 2–03, GBG 29.

5. Ibandronate with or without capecitabine in elderly patients with early breast cancer – ICE – Study / BIG 4-04, GBG 32. (see also description under WSG)

6. GAIN: German Adjuvant Intergroup Node-positive Study. A Phase III trial to compare ETC versus EC-TX and ibandronate versus observation in patients with node-positive primary breast cancer / GBG 33.

7. A randomized, multi-center, open Phase III study comparing the postoperative use of zoledronic acid versus no treatment in patients with histological tumour residuals after preoperative anthracycline and taxane-containing chemotherapy for primary breast cancer (Neo-Adjuvant Trial Add-On) / GBG 36.

8. Prospective randomized multi-center study to prevent chemotherapy-induced ovarian failure with the GnRH-agonist goserelin in young hormone-insensitive breast cancer patients receiving anthracycline-containing (neo-)adjuvant chemotherapy / GBG 37, ZORO-Study

9. A multi-centre Phase I–II study to investigate the combination of bendamustine with weekly paclitaxel as first or second line therapy in patients with anthracycline-pretreated metastatic breast cancer / GBG 38, Rita – Study.

10. A multi-center Phase II study to determine the efficacy of capecitabine as first line monochemotherapy in patients with HER-2 negative metastatic breast cancer / GBG 39, Monica – Study.

11. GeparQuattro: A randomized Phase III study exploring the efficacy of capecitabine given concomitantly or in sequence to EC – Doc with or without trastuzumab as neoadjuvant treatment of primary breast cancer. A joint study of GBG and AGO / GBG 40.

12. Randomized study comparing 6 × FEC with 3 × FEC followed by 3 × docetaxel in high-risk node-negative patients with operable breast cancer: comparison of efficacy and evaluation of clinico-pathological and biochemical markers as risk selection criteria. A joint study of AGO, the EORTC Receptor and Biomarker Group, and the GBG (GBG 42 / NNBC 3-Europe).

This section provides current contact details and a list of recent or ongoing clinical trials that the Grupo Brasileiro Cooperativo de Pesquisa em Oncologia Clínica (GBOC) participate in with other clinical trials groups, if applicable.