BackgroundMedian indebtedness at graduation is now more than $170,000 for graduates of US Medical Schools. Debate still exists as to whether higher debt levels influence students to choose high paying non-primary care specialties. Notably, no previous research on the topic has taken into account cost of attendance when constructing a debt model, nor has any research examined the non-career major life decisions that medical students face.MethodsMedical students were surveyed using an anonymous electronic instrument developed for this study. The survey was delivered through a link included in a study email and students were recruited from school wide listservs and through snowball sampling (students were encouraged to share a link to the survey with other medical students). No incentives were offered for survey completion.ResultsResponses were recorded from 102 US Allopathic medical schools (n=3,032), with 22 institutions (11 public, 11 private) meeting inclusion criteria of 10% student body response proportion (n=1,846). Students with higher debt relative to their peers at their home institution reported higher frequencies of feeling callous towards others, were more likely to choose a specialty with a higher average annual income, were less likely to plan to practice in underserved locations, and were less likely to choose primary care specialties. Students with higher aggregate amounts of medical student loan debt were more likely to report high levels of stress from their educational debt, to delay getting married and to report disagreement that they would choose to become a physician again, if given the opportunity to revisit that choice. Increases in both aggregate and relative debt were associated with delaying having children, delaying buying a house, concerns about managing and paying back educational debt, and worrying that educational debt will influence one's specialty choice.ConclusionsMedical student debt and particularly debt relative to peers at the same institution appears to influence the way that students approach major life choices like when to start a family, when to buy a home, and what specialty to choose. Future research should take into account cost of attendance when looking for the impact of medical student debt on major life choices.

Nuclear receptors comprise a large family of highly conserved transcription factors that regulate many key processes in normal and neoplastic tissues. Most nuclear receptors share a common, highly conserved domain structure that includes a carboxy-terminal ligand-binding domain (LBD). However, a sub-group of this gene family is known as the orphan nuclear receptors because to date there are no known natural ligands that regulate their activity. Many of the 25 nuclear receptors classified as orphan play critical roles in embryonic development, metabolism, and the regulation of circadian rhythm. Here, we review the emerging role(s) of orphan nuclear receptors in breast cancer, with a particular focus on two of the estrogen-related receptors (ERRα, ERRγ) and several others implicated in clinical outcome and response or resistance to cytotoxic or endocrine therapies, including the COUP-TFs, NGFI-B, DAX-1, LRH-1, and RORα. We also propose that a clearer understanding of the function of orphan nuclear receptors in mammary gland development and normal mammary tissues could significantly improve our ability to diagnose, treat, and prevent breast cancer.

Breast cancer affects 180,000 women in the United States every year, killing over 40,000 of them. The most common type of breast cancer, which expresses the Estrogen Receptor (ER+), has been clinically treated with the antiestrogen Tamoxifen (TAM) for decades. However, up to 35% of patients taking TAM may develop resistance to the drug. This may be related to the fact that ER+ breast cancers are divided into Invasive Lobular Carcinomas (ILC) and Invasive Ductal Carcinomas (IDC), which may have different mechanisms for TAM resistance. Thus, TAM resistance represents a formidable challenge in the treatment of breast cancer. TAM is an antagonist of estrogen receptor alpha (ERalpha), and prevents estrogen-dependent growth signaling in breast tissues. We have published that overexpression of the orphan nuclear receptor, estrogen related receptor gamma (ERRgamma), leads to TAM resistance in ER+ breast cancer cell lines derived from ILC. We have recently found that ERRgamma is also overexpressed in the IDC-derived RR TAM resistant cell line (but not in other models of TAM resistance). This leads us to hypothesize that other orphan nuclear receptors may have been overlooked in prior studies of TAM resistance, and that different members of the nuclear receptor superfamily play unique roles in ILC- and IDC-derived TAM resistant breast cancer. To test this hypothesis, we profiled mRNA expression of the nuclear receptor superfamily in two pairs of TAM sensitive and resistant cells: the IDC-derived MCF7 and RR, and the ILC-derived MDA-MB-134VI and TAM-R. Expression of two members of the COUP transcription factor family was significantly changed. NR2F1 (COUP-TFI) was highly overexpressed in RR cells, and NR2F2 (COUP-TFII) was highly overexpressed in both RR and TAM-R cells relative to sensitive controls. These findings are highly significant as COUP transcription factors have been implicated in embryonic stem cell pluripotency, and NR2F1 has been previously shown to interact with and enhance ERalpha activity through increasing its phosphorylation by MAPK. Therefore, overexpression of NR2F1 (and possibly NR2F2) may counteract the antagonistic effects of TAM and represent a novel pathway for TAM resistance in lobular and ductal ER+ breast cancers. Ongoing studies include gel electrophoresis to determine whether this overexpression is observed at the protein level and siRNA knockdown experiments to determine the impact of NR2F1 and NR2F2 on ERalpha phosphorylation and activity, TAM resistance, cell death, and overall survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4600.

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