Research Grants Awarded
Functional Analysis of the Cancer-Amplified Coactivator AIB3 in Hormonal Promotion of Breast Cancer
Estrogens (E) and progesterone (P), working through their receptors ER and PR, are essential for normal mammary gland (MG) development and function but can also promote breast cancer. Hormonal depletion or receptor inactivation by treatment with antagonists, are effective ways to inhibit breast cancer. Despite E and P critical role in tumor promotion, it is still unknown whether cancer initiates from cells with or without ER and PR expression. ER and PR activity is boosted or suppressed by coactivators and corepressors, respectively. AIB3 (Amplified in Breast Cancer 3) is a coactivator which gene was found to be overexpressed in different cancers. The goal of our study is to understand the specific role and molecular mechanisms of AIB3 in ER alpha and PR-regulated MG development and hormonal promotion of breast cancer. Based on these preliminary data: 1) in AIB3-/- mouse embryonic fibroblasts, ER alpha and PR transcriptional capabilities are significantly impaired, 2) AIB3 is highly expressed in mammary epithelial cells (MECs) and its expression is further induced in tumor cells, 3) AIB3 hypomorphic mouse model lacking AIB3 alpha isoform presents severe MG developmental defects, we hypothesize that AIB3 inactivation will severely affect ER alpha and PR transcriptional ability in MECs and consequently cause abnormalities in MG development and function. Furthermore, we believe that a targeted deletion of AIB3 in ER+/PR+ MECs will significantly inhibit breast tumor incidence and growth. For this study we generated conditional knock-out mice where AIB3 or/and the tumor suppressor PTEN have been uniquely deleted in ER alpha and PR-positive cells. In these animals the Cre recombinase is driven by the endogenous PR promoter. This allows a Cre targeted expression in PR positive cells, which, in the MG, express also ER alpha. Using these animals we will pursue the following specific aims: 1) to characterize AIB3 role in ER alpha and PR-mediated MG development, 2) to define AIB3 function in hormonal promotion of breast cancer. We will address the first point by analyzing MG morphology of WT or AIB3 mutant animals, in physiological conditions and after hormonal stimulation. We will deal with the second aim by first analyzing tumor incidence, latency and growth in animals with normal AIB3 but inactivated PTEN gene in ER alpha and PR-positive cells. By doing so, we will clarify whether ER alpha and PR-positive MECs can work as tumor initiating cells. Second, we will study tumor susceptibility in animals with deleted AIB3. Accomplishment of these specific aims will offer a better understanding of the cancer-amplified coactivator AIB3 in ER alpha and PR-regulated MG development, function and hormonal promotion of breast cancer. In addition, the outcome of our study will have significant implications for unraveling the biology of breast cancer and therefore developing new, more cell-specific therapeutic strategies.
Cancer is an uncontrolled cell growth caused by inherited and/or sporadic gene mutations. Mutations that promote cell survival and growth can occur: 1) in genes that are normally responsible for the inhibition of cell proliferation, in which case the tumor develops for a lack of control over cell growth or 2) in genes involved in the stimulation of cell proliferation, in which case the tumor is caused by an abnormal proliferative stimulus. As a consequence, the identification of genes that are responsible for the onset and growth of cancer is one of the most direct and effective steps towards the development of new strategies for cancer prevention, diagnosis and treatment. High levels of ovarian hormones, such as Estrogens (E) and Progesterone (P), are well known risk factors for breast cancer, since they boost mammary gland cell growth. To function, E and P bind to specific proteins called estrogen receptor (ER) and progesterone receptor (PR), which are present in the nucleus of hormone target cells. Upon hormone binding, ER and PR recruit additional proteins that can positively or negatively modulate their activity. AIB3 (Amplified in Breast Cancer 3) is a so called ?coactivator? protein, because it binds to ER and PR and turns their activity on. Since, when ER and PR are active they strongly stimulate cell growth and this may eventually promote cancer, it is possible that high AIB3 levels may be dangerously linked to tumor formation. Interestingly, AIB3 was also found to be present at high levels in different cancers, including lung, colon and breast cancers. Unfortunately, very little is known about AIB3 function in vivo, therefore in this study we will examine AIB3 involvement in the hormonal promoted mammary gland normal development and tumor formation. To address these issues I will use innovative mouse models recently generated in our laboratory to study the unique role of AIB3 in specific cells with ER and PR, where AIB3 activity may be more dangerous in breast cancer. In these animals, we will first analyze if the breast can correctly develop in the absence of AIB3, secondly and most importantly we will determine if in a mouse model that develops ER- and PR-positive breast tumors, the lack of AIB3 is sufficient to inhibit or delay tumor formation. Considering the multiple lines of evidence and our promising preliminary data, we believe that AIB3 has a critical role in normal mammary gland development and anomalous AIB3 levels may be dangerously linked to breast tumor formation. In summary, the outcome of our research will be of extreme interest and will give a significant contribution to the actual knowledge of the molecular mechanisms that lead to breast cancer formation. Moreover, our results will evaluate AIB3 as a target for suppression of breast cancer and open a new way to the development of innovative, more specific treatment for breast cancer.