APC Loss Prevents Doxorubicin-Induced Cell Death by Increasing Drug Efflux and a Chemoresistant Cell Population in Breast Cancer.

Chemoresistance is a major health concern affecting cancer patients. Resistance is multifactorial, with one mechanism being the increased expression of ABC transporters (such as MDR1 and MRP1), which are drug efflux transporters capable of preventing intracellular accumulation of drugs and cell death. Our lab showed that the loss of Adenomatous Polyposis Coli (APC) caused an intrinsic resistance to doxorubicin (DOX), potentially through an enhanced tumor-initiating cell (TIC) population and the increased activation of STAT3 mediating the expression of MDR1 in the absence of WNT being activated. Here, in primary mouse mammary tumor cells, the loss of APC decreased the accumulation of DOX while increasing the protein levels of MDR1 and MRP1. We demonstrated decreased APC mRNA and protein levels in breast cancer patients compared with normal tissue. Using patient samples and a panel of human breast cancer cell lines, we found no significant trend between APC and either MDR1 or MRP1. Since the protein expression patterns did not show a correlation between the ABC transporters and the expression of APC, we evaluated the drug transporter activity. In mouse mammary tumor cells, the pharmacological inhibition or genetic silencing of MDR1 or MRP1, respectively, decreased the TIC population and increased DOX-induced apoptosis, supporting the use of ABC transporter inhibitors as therapeutic targets in APC-deficient tumors.

Family-based lifestyle interventions: What makes them successful? A systematic literature review.

Nearly one in five young people in the United States has obesity, putting one-fifth of America's children at higher risk of having chronic health conditions and of having obesity into adulthood. Family-based lifestyle interventions (FBLI) have been proposed as effective mechanisms to improve the health through health education and the adoption of healthier behaviors. The aim of this review is to identify and summarize effective intervention activities and lessons learned that organizations can adopt when planning health promotion interventions for families, and to assess the effect of family-based lifestyle interventions on BMI z-score. A systematic review on lifestyle health-promotion interventions for families was conducted following PRISMA (Preferred Reporting Items for Systematic reviews and Meta-analyses) statements. Inclusion criteria were: duration ≥12 weeks and inclusion of family members. Summary data about the assessment tools, intervention strategies, and outcomes in parents and children were extracted and compared for all studies. A meta-analysis of BMI z-score change was conducted. Thirty-four articles were included in this review. Frequent strategies used were delivering education and training on healthy habits and well-being (94%), engaging community in the planning and implementation phases (80.6%) and providing reminders and feedback (47.2%). BMI z-score mean differences were reported in 40 cohorts and included in a meta-analysis, with no statistically significant differences between groups. The findings of this systematic review and meta-analysis indicate that components of a successful family lifestyle intervention program include duration between six to twelve months and delivery in a community setting. Other key factors include constructing a multidisciplinary team, using a mentor/role model approach, and reinforcing messaging with technology.

APC loss in breast cancer leads to doxorubicin resistance via STAT3 activation.

Resistance to chemotherapy is one of the leading causes of death from breast cancer. We recently established that loss of Adenomatous Polyposis Coli (APC) in the Mouse Mammary Tumor Virus - Polyoma middle T (MMTV-PyMT) transgenic mouse model results in resistance to cisplatin or doxorubicin-induced apoptosis. Herein, we aim to establish the mechanism that is responsible for APC-mediated chemotherapeutic resistance. Our data demonstrate that MMTV-PyMT;ApcMin/+ cells have increased signal transducer and activator of transcription 3 (STAT3) activation. STAT3 can be constitutively activated in breast cancer, maintains the tumor initiating cell (TIC) population, and upregulates multidrug resistance protein 1 (MDR1). The activation of STAT3 in the MMTV-PyMT;ApcMin/+ model is independent of interleukin 6 (IL-6); however, enhanced EGFR expression in the MMTV-PyMT;ApcMin/+ cells may be responsible for the increased STAT3 activation. Inhibiting STAT3 with a small molecule inhibitor A69 in combination with doxorubicin, but not cisplatin, restores drug sensitivity. A69 also decreases doxorubicin enhanced MDR1 gene expression and the TIC population enhanced by loss of APC. In summary, these results have revealed the molecular mechanisms of APC loss in breast cancer that can guide future treatment plans to counteract chemotherapeutic resistance.