Muestra Del Adn

J Mammary Gland Biol Neoplasia (2011) 16:89–95 DOI 10.1007/s10911-011-9216-2

TGFBR1 Signaling and Breast Cancer
Lakisha Moore-Smith & Boris Pasche

Received: 18 March 2011 / Accepted: 21 March 2011 / Published online: 5 April 2011 # Springer Science+Business Media, LLC 2011

Abstract Over the past decade mutations discovered in genes such as BRCA1, BRCA2, TP53 and PTEN, have emerged ashigh-penetrance susceptibility genes and are clinically relevant for determination of breast cancer risk. Genetic counseling and subsequent screening for mutations and gene rearrangement has improved patient outcome through early detection and prophylactic interventions in patients with familial breast cancer syndromes. However, these highpenetrance genes only account for a small fraction of thehereditary linked breast cancers. It is currently believed that low-penetrance susceptibility alleles and/or environmental factors may play an important role in the remaining cases. TGFBR1*6A (*6A) is a common hypomorphic variant of the type I TGF-β receptor gene (TGFBR1) that has been associated with risk for several forms of cancer, in particular breast cancer. Several epidemiological studies havesuggested that patients who carry the *6A allele have an increased risk of breast cancer. Furthermore, functional analysis suggests that this mutation alters TGF-β signaling and promotes tumorigenesis. Although a decade of research has provided basic information in regards to the prevalence of this mutation in several cancer types and populations the molecular underpinning of its functionaleffects are poorly understood. A better understanding of the molecular mechanism of TGFBR1 signaling in breast cancer may have an impact on breast cancer risk assessment and breast cancer prevention.

Keywords TGFBR1 . Breast cancer . TGF-β . Cancer genetics . Low-penetrance susceptibility alleles . BRCA1/2 . TP53 . PTEN . CHEK2 . Li Fraumeni syndrome . Cowden’s disease . Hereditary breast and ovariansyndrome Abbreviations ARHGAP5 Rho GTPase-activating protein 5 ATM Ataxia telangiectasia mutated CDKN Cyclin-dependent kinase inhibitor ERRB2 Human Epidermal growth factor Receptor 2 FN1 Fibronectin GWA Genome-wide association MAPK Mitogen-activated protein kinase PIK3 Phosphatidylinositol 3-kinase PTEN Phosphatase and tensin homologue rSMAD Receptor-regulated SMAD coSMAD Co-mediator SMAD iSMADInhibitory SMAD STK11 Serine/Threonine kinase TGF-β Transforming growth factor beta TGFBR Transforming growth factor beta receptor

Introduction to breast cancer Breast cancer is the second leading cause of cancer death for women living in the United States. The American Cancer Society reports that in 2010, there were more than 209,000 new cases of breast cancer and more than 40,000 deaths [1].Through advances in detection and treatment modalities, the number of breast cancer survivors has steadily increased. The high incidence and prevalence of breast cancer provides a strong rationale for studies into the biology of breast cancer. Screening recommendations,

L. Moore-Smith : B. Pasche (*) Division of Hematology/Oncology, Department of Medicine, The University of Alabama atBirmingham, 1802 6th Avenue South, NP 2566, Birmingham, AL 35294–3300, USA e-mail: Boris.Pasche@ccc.uab.edu

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J Mammary Gland Biol Neoplasia (2011) 16:89–95

including mammography, MRI in high risk women and self-breast exams, have greatly increased the number of women who are diagnosed at early stage. Breast cancer outcome depends in great part on stage of disease at the time of diagnosis.Additional screening recommendations and new predictive markers of breast cancer risk will likely further decrease breast cancer mortality because of a shift towards diagnosis of early stage breast cancer. While treatments such as surgery, radiation and immunotherapy have proven very effective for localized disease, treatment for metastatic breast cancer remains a major challenge. Of the more than...