Trastuzumab is a monoclonal antibody targeting the human epidermal growth factor receptor-2 (HER-2) protein, the mediator of an aggressive breast cancer phenotype. Trastuzumab has an important role in the treatment of metastatic breast cancer (MBC) where it improves multiple endpoints, including overall survival. More recently, striking activity is also seen in non-MBC, with substantial benefits seen in both the neoadjuvant and adjuvant settings. Experimental data has identified synergistic therapeutic effects of platinum containing chemotherapeutic regimens when combined with trastuzumab. We review the pre-clinical and rapidly evolving clinical evidence supporting platinum and trastuzumab combinations for HER-2-positive breast cancer.

Breast cancer is a multifactorial disease that is triggered by gene–environment interactions. Epidemiological research has identified alcohol consumption as a significant non-hormonal-related and consistent risk factor, and is thus a preventable cause of breast cancer. The reasons why alcohol drinking increase breast cancer risk are unclear, and several hypotheses exist. The perturbation of estrogen metabolism and response appears to one mechanism underlying the association. Alcohol consumption also increases breast density in postmenopausal women and affects sex steroid levels. Other plausible mechanisms include: (1) mutagenesis by acetaldehyde, which is a metabolite of ethanol; (2) by enhancing the susceptibility of the mammary gland to carcinogenesis by affecting DNA repair, stimulating cell proliferation or altering mammary gland structural development; (3) influencing the disposition and function of essential nutrients or dietary factors considered cancer protective (e.g. affecting folate and one-carbon metabolism pathways); (4) inducing genome instability and DNA damage; and (5) inducing oxidative damage via ethanol or estrogen metabolism. To better understand the etiological nature of the effect of alcohol on breast carcinogenesis, further studies at the cellular and molecular levels on the interaction between ethanol and other risk factors, estrogen, carcinogens are needed.

Citation of original article:

C. Wang et al. Cancer Research 2005; 65(15): 6557–6567.

Abstract of the original article:

The cyclin D1 gene is frequently overexpressed in human breast cancer and is capable of inducing mammary tumorigenesis when overexpressed in transgenic mice. The BRCA1 breast tumor susceptibility gene product inhibits breast cancer cellular growth and the activity of several transcription factors. Herein, cyclin D1 antagonized BRCA1-mediated repression of estrogen receptor α(ERα)-dependent gene expression. Cyclin D1 repression of BRCA1 function was mediated independently of its cyclin-dependent kinase, retinoblastoma protein, or p160 (SRC-1) functions in human breast and prostate cancer cells. In vitro, cyclin D1 competed with BRCA1 for ERα binding. Cyclin D1 and BRCA1 were both capable of binding ERα in a common region of the ERα hinge domain. A novel domain of cyclin D1, predicted to form a helix-loop-helix structure, was required for binding to ERα and for rescue of BRCA1-mediated ERα transcriptional repression. In chromatin immunoprecipitation assays, 17β-estradiol (E2) enhanced ERα and cyclin D1 recruitment to an estrogen response element (ERE). Cyclin D1 expression enhanced ERα recruitment to an ERE. E2 reduced BRCA1 recruitment and BRCA1 expression inhibited E2-induced ERα recruitment at 12 h. Cyclin D1 expression antagonized BRCA1 inhibition of ERα recruitment to an ERE, providing a mechanism by which cyclin D1 antagonizes BRCA1 function at an ERE. As cyclin D1 abundance is regulated by oncogenic and mitogenic signals, the antagonism of the BRCA1-mediated ERα repression by cyclin D1 may contribute to the selective induction of BRCA1-regulated target genes.