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Biomedical subjects

Sean C Dowdy

Publications and source records attributed to Sean C Dowdy.

23 records · Page 2Linked to original sources
PubMed2003

HER2/Neu- and TAK1-mediated up-regulation of the transforming growth factor beta inhibitor Smad7 via the ETS protein ER81.

The cytokine transforming growth factor beta (TGF-beta) plays an important role in preventing tumor formation by blocking cell cycle progression. Accordingly, many cancers demonstrate mutations in TGF-beta signaling components or enhanced expression of inhibitors of the TGF-beta pathway such as Smad7. In this report we show that the oncoprotein HER2/Neu is able to collaborate with the ETS transcription factor ER81 to activate Smad7 transcription in breast, endometrial, and ovarian cancer cell lines. ER81 binds to two ETS sites within the Smad7 promoter, and mutation of one of these ETS sites greatly decreases Smad7 induction by HER2/Neu and ER81. Furthermore, we show that Smad7 activation involves the processing of signals from HER2/Neu to ER81 via the ERK mitogen-activated protein kinase pathway. Thus, we have uncovered a novel mechanism by which oncogenic HER2/Neu, in collaboration with ER81, can induce carcinogenesis through Smad7 up-regulation. Moreover, we show that TAK1, a TGF-beta-activated protein kinase, stimulates ER81 via the p38 mitogen-activated protein kinase pathway and thereby induces the Smad7 promoter. This suggests that attenuation of TGF-beta signaling by activating Smad7 transcription may proceed not only through TGF-beta receptor-regulated Smad proteins but also through an independent pathway involving ER81 and TAK1.

Binding Sites↗
PubMed2003

Long-term follow-up of women with ovarian cancer after positive second-look laparotomy.

OBJECTIVE: Previous reports indicate that cytoreduction and salvage therapy with P32 or whole abdominal radiation may improve survival in patients with positive findings at second-look laparotomy (SLL). The aim of this investigation was to determine whether these findings held true with extended follow-up and a larger patient cohort. METHODS: From 1977 (the year platinum-based chemotherapy was introduced to our institution) to 1989, 150 patients had persistent disease at SLL. Relevant clinical information was extracted through retrospective chart review. RESULTS: One hundred forty-five patients were followed until death, with a median follow-up of 15.4 years for the 5 living patients. Median actuarial survival from the time of SLL was 18 months. Tumor grade (P = 0.003) and pre- and post-SLL tumor size (P < 0.0001) were significant determinants of survival by univariate analysis. Patients with microscopic disease or those with < or =1 cm disease rendered microscopic at SLL had improved survival relative to those with < or =1 cm and macroscopic disease following SLL (P = 0.03) (median survivals of 3.3, 2.5, and 1.4 years, respectively). In contrast, median survival of those with >1 cm disease cytoreduced to microscopic disease was no different than those with macroscopic residual, even if < or =1 cm (1.3 and 1.0 years, respectively). After adjusting for tumor size, salvage treatment was not a significant predictor of survival. CONCLUSION: With long-term follow-up there was no suggestion that the type of salvage therapy (e.g., P32 or WART) influenced survival. Rather, low-grade disease and low tumor burdens following cytoreduction were associated with improved survival on multivariate analysis.

Aged↗
PubMed2002

Multimodal therapy including neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) for stage IIB to IV cervical cancer.

OBJECTIVE: The purpose of this study was to determine the survival rates and toxicity levels that are associated with multimodal therapy (including neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin [MVAC]) in patients with stage IIB to IVB cervical cancer. STUDY DESIGN: We retrospectively reviewed the cases of 49 patients who were treated between 1989 and 1997 with neoadjuvant MVAC for advanced cervical cancer. RESULTS: The clinical response rate was 90% (27 partial responders, 17 complete responders). Grade 3 or greater toxicity was mostly limited to neutropenia; no deaths were attributed to MVAC. Combined therapy after MVAC included operation in 34 patients (69%) and radiation in 41 patients (84%). Twenty-one patients (43%) had <2 cm residual tumor at histologic evaluation. Pelvic control was achieved in 86% of patients. Five-year disease-specific survival for patients with stage III disease was 60%. CONCLUSION: For patients with advanced cervical cancer, neoadjuvant MVAC had a high response rate (90%) and an acceptable toxicity level. Compared with historic control subjects, multimodal treatment may be associated with improved rates of pelvic control.

Adult↗
PubMedDate not supplied

HER-2/neu overexpression and hormone dependency in endometrial cancer: analysis of cohort and review of literature.

BACKGROUND: Overexpression of HER-2/neu (HER) is associated with unfavorable prognoses in both endometrial and breast cancer. MATERIALS AND METHODS: To determine whether an association exists between HER expression and markers of hormone dependency in endometrial cancers, we subjected hysterectomy specimens from 125 patients to immunohistochemical staining for HER. HER was visually interpreted as negative/weakly positive (HER-) versus strongly positive (HER+). Estrogen receptor (ER) and progesterone receptor (PR) levels were quantitated on fresh tissue using a dextran-coated charcoal assay. RESULTS: HER+ was observed in 12% of endometrioid tumors and 22% of nonendometrioid tumors (p = 0.07). Mean ER and PR levels were 255 fmol/mg and 457 fmol/mg in endometrioid tumors, compared with 74 and 104 in nonendometrioid tumors (p < 0.01). Hyperplasia associated with the tumor was related to high levels of both ER and PR (p < 0.05), but not with HER expression. Age was significantly related to high levels of ER (p = 0.007). Both recurrence and death rates were significantly associated with low levels of ER and PR (p < 0.01). Mean ER and PR levels were 270 and 466 fmol/mg, respectively, in HER-tumors, compared with 95 (p = 0.14) and 138 fmol/mg (p = 0.02) in HER+ tumors. CONCLUSION: HER overexpression may be an important step in hormone-independent growth and proliferation in a subgroup of endometrial cancers.

Adult↗