Project 2: Molecular Mechanisms of Estrogen and Progesterone-Dependent Cell Motility and Proliferation in Breast Cancer

Access to Care: Since 2005, Avon Foundation has provided essential funding supporting a collaborative, comprehensive access to care program between Northwestern University and Erie Family Health Center. Over the past 2 years, significant expansion of the Erie Family Health Center and its patient population has increased the role of care coordination. Additionally, the patient population has increased in diversity by geography, race/ethnicity and language. Consequently, providing breast healthcare has become more challenging. With continued Avon support, we will address these challenges through the optimal application of existing resources. Our goal is to develop efficient and effective patient navigation services with technological aids where possible. In this renewal, we seek support for: Continued patient navigation for women overdue for screening mammograms and those requiring diagnostic breast care; development and dissemination of navigation services through patient portal technology: reminders of overdue services, access to educational materials, increased total number of breast health services, without increasing cost or personnel. Translational Breast Cancer Biology Program: We continue to make progress on therapeutically targetable mechanisms related to steroid hormone-dependency of breast cancer. The following three projects explore the molecular links between estrogen, progesterone and metabolism. Project 1: Personalized cancer therapy aims to identify specific subgroups of cancer patients that will benefit from specific therapeutic strategies. Estrogen receptor positive (ER+) invasive ductal cancers are the most common human breast malignancies and are grouped into luminal A versus luminal B. Luminal B, exhibit a higher proliferative capacity, are poorly differentiated, and are more likely to recur. It is increasingly clear that a subgroup of luminal B tumors are endocrine resistant and fail to respond to Tamoxifen. This resistance may explain the increased risk of recurrence in this subgroup of women despite the use of anti-hormonal therapy. We have shown that breast cancer cells lacking SIRT3 exhibit resistant to Tamoxifen, providing a model to identify agents that may reverse the Tamoxifen resistance observed in luminal B breast cancer. Based on these results it is hypothesized that either the dysregulation of SIRT3, or a SIRT3 downstream deacetylation target, plays a role, at least in some part, in the development of an endocrine resistant breast tumor cell phenotype. In addition, it is proposed to develop and validate agents that restore SIRT3 as well as reverse the resistance to Tam that is observed in women with luminal B cancers. Project 2: Breast cancer is an estrogen- and progesterone-dependent disease with large variations in responsiveness to hormonal treatment. Using in vitro Chip-seq techniques in breast cancer cell lines and in vivo analyses of breast tumor samples linked with cutting-edge genome-wide techniques, we identified two novel estrogen and progesterone-responsive genes, i.e., sushi domain-containing protein 3 (SUSD3) and adipophilin (PLIN2). Our preliminary findings suggested that SUSD3 regulates estrogen-dependent cell proliferation, survival, adhesion and motility. On the other hand, PLIN2 is most likely a tumor suppressor. However, the breast tissue distribution pattern of SUSD3 and PLIN2 and in vivo links between SUSD3, PLIN2, and estrogen and progesterone receptors (ERα and PGR) remain unexplored. Moreover, functional and clinical roles of SUSD3 and PLIN2 in breast cancer proliferatio