Post-Hypoxic Cells Promote Metastatic Recurrence after Chemotherapy Treatment in TNBC.

Hypoxia occurs in 90% of solid tumors and is associated with treatment failure, relapse, and mortality. HIF-1α signaling promotes resistance to chemotherapy in cancer cell lines and murine models via multiple mechanisms including the enrichment of breast cancer stem cells (BCSCs). In this work, we utilize a hypoxia fate-mapping system to determine whether triple-negative breast cancer (TNBC) cells that experience hypoxia in the primary tumor are resistant to chemotherapy at sites of metastasis. Using two orthotopic mouse models of TNBC, we demonstrate that cells that experience intratumoral hypoxia and metastasize to the lung and liver have decreased sensitivity to doxorubicin and paclitaxel but not cisplatin or 5-FU. Resistance to therapy leads to metastatic recurrence caused by post-hypoxic cells. We further determined that the post-hypoxic cells that metastasize are enriched in pathways related to cancer stem cell gene expression. Overall, our results show that even when hypoxic cancer cells are reoxygenated in the bloodstream they retain a hypoxia-induced cancer stem cell-like phenotype that persists and promotes resistance and eventually recurrence.

Hypoxia Alters the Response to Anti-EGFR Therapy by Regulating EGFR Expression and Downstream Signaling in a DNA Methylation-Specific and HIF-Dependent Manner.

Intratumoral hypoxia occurs in 90% of solid tumors and is associated with a poor prognosis for patients. Cancer cells respond to hypoxic microenvironments by activating the transcription factors, hypoxia-inducible factor 1 (HIF1) and HIF2. Here, we studied the unique gene expression patterns of 31 different breast cancer cell lines exposed to hypoxic conditions. The EGFR, a member of the ErbB (avian erythroblastosis oncogene B) family of receptors that play a role in cell proliferation, invasion, metastasis, and apoptosis, was induced in seven of the 31 breast cancer cell lines by hypoxia. A functional hypoxia response element (HRE) was identified, which is activated upon HIF1 binding to intron 18 of the EGFR gene in cell lines in which EGFR was induced by hypoxia. CpG methylation of the EGFR HRE prevented induction under hypoxic conditions. The HRE of EGFR was methylated in normal breast tissue and some breast cancer cell lines, and could be reversed by treatment with DNA methyltransferase inhibitors. Induction of EGFR under hypoxia led to an increase in AKT, ERK, and Rb phosphorylation as well as increased levels of cyclin D1, A, B1, and E2F, and repression of p21 in an HIF1α-dependent manner, leading to cell proliferation and migration. Also, increased EGFR expression sensitized cells to EGFR inhibitors. Collectively, our data suggest that patients with hypoxic breast tumors and hypomethylated EGFR status may benefit from EGFR inhibitors currently used in the clinic. SIGNIFICANCE: Hypoxia sensitizes breast cancer cells to EGFR inhibitors in an HIF1α- and a methylation-specific manner, suggesting patients with hypoxic tumors may benefit from EGFR inhibitors already available in the clinic. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/22/4998/F1.large.jpg.

A New Method to Assess Asymmetry in Fingerprints Could Be Used as an Early Indicator of Type 2 Diabetes Mellitus.

BACKGROUND: Inexpensive screening tools are needed to identify individuals predisposed to developing diabetes mellitus (DM). Such early identification coupled with an effective intervention could help many people avoid the substantial health costs of this disease. We investigated the hypothesis that fluctuating asymmetry (FA) in fingerprints is an indicator of type 2 diabetes mellitus (T2DM). METHODS: Participants with T2DM, with T1DM, and without any indication or known family history of diabetes were fingerprinted with a Crossmatch Verifier 320 LC scanner. Asymmetry scores for each finger pair were assessed using both pattern analysis (ridge counts), and a wavelet-based analysis. RESULTS: Both methods for scoring asymmetry predicted risk of T2DM for finger pair IV, controlling for gender and age. AUC scores were significantly greater than the null for pattern asymmetry scores (finger IV AUC = 0.74), and wavelet asymmetry scores for finger pair IV (AUC = 0.73) and finger pair V (AUC = 0.73), for predicting T2DM. In addition, wavelet asymmetry scores for finger pair IV (AUC = 0.80) and finger pair V (AUC = 0.85) significantly predicted risk of T1DM. CONCLUSIONS: A diagnostic tool based on FA in the fingerprints of finger pair IV, measured using a wavelet analysis could be developed for predicting risk prior to associated health problems for both T2DM and T1DM. In addition, given that that the prints for fingers IV and V develop during the 14-17 weeks of gestation, we predict that interventions during this time period of pregnancy will be most successful.