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Wake Forest, NC, United States

Colonna S.V.,Huntsman Cancer Institute | Higgins A.K.,Wake Forest Comprehensive Cancer Center | Alvarez J.,Vanderbilt University | Saville B.R.,Vanderbilt University | And 2 more authors.
Clinical Breast Cancer | Year: 2015

Introduction: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer with higher recurrence rates than other breast cancer subtypes. Increasing numbers of women are being diagnosed with early-stage breast cancer because of improvements in screening mammography. TNBC is known to be highly sensitive to chemotherapy; however, the benefit of adjuvant chemotherapy among women with ≤ 1-cm, lymph node-negative TNBC is unknown. Materials and Methods: We evaluated the recurrence rates and recurrence-free survival of 437 women diagnosed with stage T1a-T1bN0 breast cancer from 1997 to 2009 at 2 institutions, with a median follow-up time of 6.2 years. Furthermore, we examined the treatment regimens of these women and evaluated the association of adjuvant chemotherapy with recurrence-free survival. Results: Chemotherapy was administered more often to younger women and to women with high-grade, human epidermal growth factor receptor 2-positive or TNBC. Recurrence-free survival did not differ significantly between TNBC and estrogen receptor-positive breast cancer (hazard ratio [HR], 0.33; 95% confidence interval [CI], 0.10-1.04; P = .058). After appropriate adjustments, no significant differences were detected in recurrence-free survival between the women who had received chemotherapy and those who had not among the women with TNBC (P = .132) or within any of the breast cancer subtypes (HR, 0.6; 95% CI, 0.2-1.9; P = .392). Conclusion: Prospective trials of this subcentimeter node-negative breast cancer population are warranted to guide adjuvant chemotherapy decisions. © 2015.

Barlow K.D.,Medical Center Boulevard | Sanders A.M.,Medical Center Boulevard | Soker S.,Wake Forest Comprehensive Cancer Center | Soker S.,Wake Forest Institute for Regenerative Medicine | And 3 more authors.
Cancer Microenvironment | Year: 2013

The induction of tumor vasculature, known as the 'angiogenic switch', is a rate-limiting step in tumor progression. Normal blood vessels are composed of two distinct cell types: endothelial cells which form the channel through which blood flows, and mural cells, the pericytes and smooth muscle cells which serve to support and stabilize the endothelium. Most functional studies have focused on the responses of endothelial cells to pro-angiogenic stimuli; however, there is mounting evidence that the supporting mural cells, particularly pericytes, may play key regulatory roles in both promoting vessel growth as well as terminating vessel growth to generate a mature, quiescent vasculature. Tumor vessels are characterized by numerous structural and functional abnormalities, including altered association between endothelial cells and pericytes. These dysfunctional, unstable vessels contribute to hypoxia, interstitial fluid pressure, and enhanced susceptibility to metastatic invasion. Increasing evidence points to the pericyte as a critical regulator of endothelial activation and subsequent vessel development, stability, and function. Here we discuss both the stimulatory and inhibitory effects of pericytes on the vasculature and the possible utilization of vessel normalization as a therapeutic strategy to combat cancer. © 2012 Springer Science+Business Media B.V.

Palmer N.R.A.,San Francisco General Hospital | Weaver K.E.,Social science and Health Policy | Hauser S.P.,Wake Forest Comprehensive Cancer Center | Lawrence J.A.,Wake Forest Comprehensive Cancer Center | And 3 more authors.
Supportive Care in Cancer | Year: 2015

Purpose: Despite recommendations for breast cancer survivorship care, African American women are less likely to receive appropriate follow-up care, which is concerning due to their higher mortality rates. This study describes differences in barriers to follow-up care between African American and White breast cancer survivors. Methods: We conducted a mailed survey of women treated for non-metastatic breast cancer in 2009–2011, 6–24 months post-treatment (N = 203). Survivors were asked about 14 potential barriers to follow-up care. We used logistic regression to explore associations between barriers and race, adjusting for covariates. Results: Our participants included 31 African American and 160 White survivors. At least one barrier to follow-up care was reported by 62 %. Compared to White survivors, African Americans were more likely to identify barriers related to out-of-pocket costs (28 vs. 51.6 %, p = 0.01), other health care costs (21.3 vs. 45.2 %, p = 0.01), anxiety/worry (29.4 vs. 51.6 %, p = 0.02), and transportation (4.4 vs. 16.1 %, p = 0.03). After adjustment for covariates, African Americans were three times as likely to report at least one barrier to care (odds ratio (OR) = 3.3, 95 % confidence interval (CI) = 1.1–10.1). Conclusions: Barriers to care are common among breast cancer survivors, especially African American women. Financial barriers to care may prevent minority and underserved survivors from accessing follow-up care. Enhancing insurance coverage or addressing out-of-pocket costs may help address financial barriers to follow-up care among breast cancer survivors. Psychosocial care aimed at reducing fear of recurrence may also be important to improve access among African American breast cancer survivors. © 2015, Springer-Verlag Berlin Heidelberg.

Burger K.L.,Wake Forest Comprehensive Cancer Center | Learman B.S.,Wake Forest Comprehensive Cancer Center | Boucherle A.K.,Wake Forest Comprehensive Cancer Center | Sirintrapun S.J.,Wake Forest Comprehensive Cancer Center | And 4 more authors.
Prostate | Year: 2014

BACKGROUND The Src tyrosine kinase substrate and adaptor protein Tks5 had previously been implicated in the invasive phenotype of normal and transformed cell types via regulation of cytoskeletal structures called podosomes/ invadopodia. The role of Src-Tks5 signaling in invasive prostate cancer, however, had not been previously evaluated. METHODS We measured the relative expression of Tks5 in normal (n = 20) and cancerous (n = 184, from 92 patients) prostate tissue specimens by immunohistochemistry using a commercially available tumor microarray. We also manipulated the expression and activity of wild-type and mutant Src and Tks5 constructs in the LNCaP and PC-3 prostate cancer cell lines in order to ascertain the role of Src-Tks5 signaling in invadopodia development, matrix-remodeling activity, motility, and invasion. RESULTS Our studies demonstrated that Src was activated and Tks5 upregulated in high Gleason score prostate tumor specimens and in invasive prostate cancer cell lines. Remarkably, overexpression of Tks5 in LNCaP cells was sufficient to induce invadopodia formation and associated matrix degradation. This Tks5-dependent increase in invasive behavior further depended on Src tyrosine kinase activity and the phosphorylation of Tks5 at tyrosine residues 557 and 619. In PC-3 cells we demonstrated that Tks5 phosphorylation at these sites was necessary and sufficient for invadopodia-associated matrix degradation and invasion. CONCLUSIONS Our results suggest a general role for Src-Tks5 signaling in prostate tumor progression and the utility of Tks5 as a marker protein for the staging of this disease. Prostate 74:134-148, 2014. © 2013 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Choudhary M.,Medical Center Boulevard | Choudhary M.,Duke Eye Center | Naczki C.,Medical Center Boulevard | Chen W.,Medical Center Boulevard | And 5 more authors.
BMC Cancer | Year: 2015

Background: Proper functional association between mural cells and endothelial cells (EC) causes EC of blood vessels to become quiescent. Mural cells on tumor vessels exhibit decreased attachment to EC, which allows vessels to be unstable and proliferative. The mechanisms by which tumors prevent proper association between mural cells and EC are not well understood. Since gap junctions (GJ) play an important role in cell-cell contact and communication, we investigated whether loss of GJ plays a role in tumor-induced mural cell dissociation. Methods: Mural cell regulation of endothelial proliferation was assessed by direct co-culture assays of fluorescently labeled cells quantified by flow cytometry or plate reader. Gap junction function was assessed by parachute assay. Connexin 43 (Cx43) protein in mural cells exposed to conditioned media from cancer cells was assessed by Western and confocal microscopy; mRNA levels were assessed by quantitative real-time PCR. Expression vectors or siRNA were utilized to overexpress or knock down Cx43. Tumor growth and angiogenesis was assessed in mouse hosts deficient for Cx43. Results: Using parachute dye transfer assay, we demonstrate that media conditioned by MDA-MB-231 breast cancer cells diminishes GJ communication between mural cells (vascular smooth muscle cells, vSMC) and EC. Both protein and mRNA of the GJ component Connexin 43 (Cx43) are downregulated in mural cells by tumor-conditioned media; media from non-tumorigenic MCF10A cells had no effect. Loss of GJ communication by Cx43 siRNA knockdown, treatment with blocking peptide, or exposure to tumor-conditioned media diminishes the ability of mural cells to inhibit EC proliferation in co-culture assays, while overexpression of Cx43 in vSMC restores GJ and endothelial inhibition. Breast tumor cells implanted into mice heterozygous for Cx43 show no changes in tumor growth, but exhibit significantly increased tumor vascularization determined by CD31 staining, along with decreased mural cell support detected by NG2 staining. Conclusions: Our data indicate that i) functional Cx43 is required for mural cell-induced endothelial quiescence, and ii) downregulation of Cx43 GJ by tumors frees endothelium to respond to angiogenic cues. These data define a novel and important role for maintained Cx43 function in regulation of vessel quiescence, and suggest its loss may contribute to pathological tumor angiogenesis. © 2015 Choudhary et al.

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