Over 75% of newly diagnosed cases of breast cancer (BC) occur in postmenopausal (PM) women. Obesity is associated with an increased risk and a poor prognosis of BC in PM women. After menopause, the risk of BC is ~50% higher in obese women than in those who are not. The mechanisms underlying obesity-related breast tumor growth are not known and strategies to alleviate the adverse effects of obesity on breast tumor development are nonexistent. Unfortunately, very few studies have focused on the effects of obesity on PM BC. We will test the novel hypothesis that obesity promotes the escape from breast tumor dormancy and promotes tumor growth by facilitating the acquisition of the vascular phenotype in PM women. It is of significant clinical interest to understand the mechanisms by which dormant tumors become clinically detectable ones, to learn how obesity affects this developmental step and to identify those women at high risk for developing active BC. The novel studies proposed here address these goals within the context of the unique convergence of obesity, breast tumor dormancy and menopause. Our preliminary studies suggest that dormant human BC cell lines develop an active angiogenic phenotype, both biochemically and functionally, when treated with adipocyte-conditioned media. The studies proposed in Aim 1 will determine the mechanisms by which adipocytes mediate this activity and whether adipocytes isolated from pre- and post-menopausal obese human subjects differ in their ability to induce the acquisition of the vascular phenotype.
In Aim 2, we will utilize three clinically relevant breat tumor mouse models of differing menopausal status to determine whether increased adiposity results in the escape from breast tumor dormancy and breast tumor progression, to identify the mechanisms underlying breast tumor development in these cases and to discover urinary biomarkers of this earliest stage in breast tumor growth.
In Aim 3, we will leverage our experience in the discovery of non- invasive cancer biomarkers to complement these animal studies with those in patients. We will determine whether urinary biomarkers predict the escape from tumor dormancy and the acquisition of the angiogenic phenotype in obese and non-obese women and in women who do/do not undergo bariatric surgery. We have brought together a unique and accomplished multidisciplinary team of scientists and clinicians to conduct the studies described within the context of the following Specific Aims: 1. to determine whether adipocytes induce the acquisition of the angiogenic phenotype in dormant BC cells 2. To determine whether obesity regulates the escape from tumor dormancy in PM BC 3. To determine whether the presence of urinary biomarkers of BC and neovascularization serve as sentinels of the escape from breast tumor dormancy in animal models of BC and in patients Taken together, these studies could result in the development of novel therapeutic, diagnostic and prognostic strategies and improved BC patient survival and may ultimately be applicable to other human cancers as well.
Remarkably, over 75% of newly diagnosed cases of breast cancer occur in postmenopausal women, with obesity being associated with an increased risk of breast cancer in women of postmenopausal age as well as with an overall poor prognosis. Why this is the case, and what the physiological events are that result in this striking and underappreciated situation, are unknown; strategies to alleviate the adverse effects of obesity on breast tumors in postmenopausal women are nonexistent. Using novel human breast cancer cell lines and mouse models, we intend to (1) test our hypothesis that obesity in postmenopausal women drives the awakening of dormant (sleepy) tumors in the breasts of these women thereby allowing the tumors to grow and to progress into clinically relevant disease and (2) to determine whether we can noninvasively detect this key step in a tumor's lifetime in order to treat it earlier.
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