• CYCLIN D1

Cyclin D1 is a key cell cycle regulatory protein for the mammalian G₁–S phase transition and is involved in the regulation of proliferation and differentiation. The expression of cyclin D1 is regulated by a coordinated cascade of intracellular events in response to extracellular signaling. In organized epithelia, the decreased expression of cyclin D1 after proliferation is necessary for ordered differentiation. The proper balance of proliferation and differentiation is crucial for the maintenance of tissue homeostasis. Deregulated cyclin D1 expression promotes genetic instability in vitro and tumorigenesis in vivo. Overexpression and/or amplification of the cyclin D1 gene is associated with poor prognosis.

Cyclin D1 in breast cancer

Endocrine therapy is the most effective treatment for women with hormone receptor–positive breast cancer. For more than 20 years, the antiestrogen tamoxifen has been the established standard of care in adjuvant endocrine therapy. In the adjuvant treatment of endocrine-responsive breast cancer, 5 years of tamoxifen almost halves the annual recurrence rate and reduces the annual breast cancer death rate by a third. Although aromatase inhibitors have recently been shown to be even more effective, tamoxifen remains an important part of the endocrine treatment armamentarium and is still the only option in many areas around the world. Tamoxifen therapy is effective in many patients but de novo and acquired resistance remains a major problem. A considerable fraction of patients do not respond to tamoxifen despite having estrogen receptor–positive tumors. These patients may need other therapeutic interventions. Therefore, the ability to predict outcome of tamoxifen treatment should significantly improve the management of early-stage breast cancer. Besides the central role in cell cycle regulation, cyclin D1 directly affects the estrogen receptor and may be involved in response to estrogens and antiestrogens. Cyclin D1 has been shown to bind to the estrogen receptor and to activate the receptor in a ligand-independent fashion. In vitro studies have linked tamoxifen resistance to the expression of cyclin D1 in cell lines. Overexpression of cyclin D1 is observed in ∼50% of breast cancer specimens and the corresponding CCND1 gene is amplified in 15%. In several clinical studies, early relapse and shorter survival were observed in women with cyclin D1–positive breast cancer who received tamoxifen treatment. The purpose of our study was to determine the clinical relevance of cyclin D1 in early-stage, hormone receptor–positive breast cancer patients who had been enrolled into two randomized clinical trials and treated with adjuvant tamoxifen-based therapy. Over the last 20 years, tamoxifen has been the standard of care for women with hormone receptor–positive breast cancer. Although several recent studies suggested that aromatase inhibitor therapy may be a slightly more effective endocrine strategy against hormone-dependent breast cancer, tamoxifen may still play an important role in the adjuvant endocrine treatment of these patients. Some patients are unsuitable for aromatase inhibitor therapy due to the side effects of the agents; others may be unsuitable due to preexisting bone problems, which many consider an aromatase inhibitor contraindication. The optimal adjuvant treatment for such patients has not yet been established. Furthermore, in many parts of the worlds, tamoxifen remains the only economically affordable treatment option for women with endocrine-responsive breast cancer for health economic reasons. In addition, endocrine intervention in low-risk breast cancer patients may need to be continued for longer periods, as we increasingly understand the biology of breast carcinoma as a chronic disease and the need for extended adjuvant intervention to prevent the late risk of relapse.

• CDK4
• BUB1B
• CENPA
• NEK2
• RACGAP1

• RRM2

RRM2 is well-known as small subunit of RNR, a rate-limiting enzyme for dNDP synthesis required for DNA replication . High RNR enzymatic activity is associated with tumor progression and resistance to various cellular stressors such as chemotherapeutic agents and ionizing radiation. Increased RRM2 and RNR enzymatic activity were reported to present in highly metastatic tumor cells and tissues . Therefore, RRM2 is also an important therapeutic target for DNA replication-dependent diseases such as cancer. Recently, many studies have demonstrated that RRM2 plays additional roles in determining the malignant potential of tumor cells. For example, elevated expression of RRM2 has been found to increase the drug-resistant properties of cancer cells and significantly enhance the invasive potential of many human cancer cells, whereas knockdown of RRM2 expression results in the reversal of drug-resistance and suppressed tumor growth, and decreased metastasis potential. Interestingly, two recent studies have found that overexpression of RRM1 suppresses invasion and metastasis formation of tumors through induction of PTEN pathway.