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188


Distinct function of androgen receptor coactivator ARA70alpha and ARA70beta in mammary gland development, and in breast cancer

Wu, Xinyu; Chen, Fei; Sahin, Aysegul; Albarracin, Constance; Pei, Zhiheng; Zou, Xuanyi; Singh, Baljit; Xu, Ruliang; Daniels, Garrett; Li, Yirong; Wei, Jianjun; Blake, Marvin; Schneider, Robert J; Cowin, Pamela; Lee, Peng
Steroid receptor coactivators are important in regulating the function of the receptors in endocrine organ development and in cancers, including breast. Androgen receptor (AR) coactivator ARA70, was first identified as a gene fused to the ret oncogene and later characterized as an AR coactivator. We previously reported that the full length ARA70alpha functions as a tumor suppressor gene and that ARA70beta functions as an oncogene in prostate cancer. Here we show that both ARA70alpha and ARA70beta function as AR and estrogen receptor (ER) coactivators in breast cancer cells. However, ARA70alpha and ARA70beta serve different functions in mammary gland development and breast cancer tumorigenesis. We observed hypoplastic development of mammary glands in MMTV driven ARA70alpha transgenic mice and overgrowth of mammary glands in ARA70beta transgenic mice at virgin and pregnant stages. We determined that ARA70alpha inhibited cell proliferation, and that ARA70beta promotes proliferation in MCF7 breast cancer cells. These effects were observed in hormone-free media, or in media with androgen or estrogen, though to varying degrees. Additionally, we observed that ARA70beta strongly enhanced the invasive ability of MCF7 breast cancer cells in in vitro Matrigel assays. Significantly, decreased ARA70alpha expression is associated with increased tendency of breast cancer metastasis. In summary, ARA70alpha and ARA70beta have distinct effects in mammary gland development and in the progression of breast cancer
PMID: 20814820
ISSN: 1573-7217
CID: 138162

The role of health system factors in delaying final diagnosis and treatment of breast cancer in Mexico City, Mexico

Bright, Kristin; Barghash, Maya; Donach, Martin; de la Barrera, Marcos Gutierrez; Schneider, Robert J; Formenti, Silvia C
In Mexico, breast cancer is the leading cancer-related death among women and most cases are diagnosed at advanced stages (50-60%). We hypothesized health system factors could be partly responsible for this delay and performed a prospective review of 166 new breast cases at a major public hospital in Mexico City. Our analysis confirmed the prevalence of locally advanced and metastatic disease (47% of patients). A subset analysis of 32 women with confirmed stage I-IIIC breast cancer found an average time interval of 1.8 months from symptom onset to first primary care consultation (PCC), with an additional 6.6 months from first PCC to confirmed diagnosis, and 0.6 months from diagnosis to treatment initiation. Patients underwent an average of 7.9 clinic visits before confirmed diagnosis. Findings suggest that protracted referral time from primary to specialty care accounts for the bulk of delay, with earlier stage patients experiencing longer delays. These findings reveal a critical need for further study and exploration of interventions
PMID: 21371885
ISSN: 1532-3080
CID: 130301

Over-expression of Translation Initiation Factor eIF4G Confers Robust Radioresistance to the Cancer Stem Cell Population in Inflammatory Breast Cancer [Meeting Abstract]

Connolly, EP; Silvera, D; Badura, ML; Venuto, T; Schneider, RJ
ISI:000296411700169
ISSN: 0360-3016
CID: 2792772

TORC1/2 Inhibition with Concurrent Radiation Controls Inflammatory Breast Cancer in a Preclinical Animal Model Through Selective Blockade of Translation [Meeting Abstract]

Connolly, EP; Silvera, D; Venuto, T; Sawai, A; Schneider, RJ
ISI:000296411701628
ISSN: 0360-3016
CID: 2792782

Preoperative concurrent paclitaxel-radiation in locally advanced breast cancer: pathologic response correlates with five-year overall survival

Adams, Sylvia; Chakravarthy, A Bapsi; Donach, Martin; Spicer, Darcy; Lymberis, Stella; Singh, Baljit; Bauer, Joshua A; Hochman, Tsivia; Goldberg, Judith D; Muggia, Franco; Schneider, Robert J; Pietenpol, Jennifer A; Formenti, Silvia C
We have previously demonstrated high pathologic response rates after neoadjuvant concurrent chemoradiation in patients with locally advanced breast cancer (LABC). We now report disease-free survival (DFS) and overall survival (OS) in the context of pathologic response. 105 LABC patients (White 46%, Non-White 54%) were treated with paclitaxel (30 mg/m(2) intravenously twice a week) for 10-12 weeks. Daily radiotherapy was delivered to breast, axillary, and supraclavicular lymph nodes during weeks 2-7 of paclitaxel treatment, at 1.8 Gy per fraction to a total dose of 45 Gy with a tumor boost of 14 Gy at 2 Gy/fraction. Pathological complete response (pCR) was defined as the absence of invasive cancer in breast and lymph nodes and pathological partial response (pPR) as the persistence of <10 microscopic foci of invasive carcinoma in breast or lymph nodes. Pathologic response (pCR and pPR) after neoadjuvant chemoradiation was achieved in 36/105 patients (34%) and was associated with significantly better DFS and OS. Pathological responders had a lower risk of recurrence or death (HR = 0.35, P = 0.01) and a longer OS (HR = 4.27, P = 0.01) compared with non-responders. Median DFS and OS were 57 and 84 months for non-responders, respectively, and have not yet been reached for responders. Importantly, pathologic response was achieved in 54% of patients with HR negative tumors (26/48). In conclusion, pathologic response to concurrent paclitaxel-radiation translated into superior DFS and OS. Half of the patients with HR negative tumors achieved a pathologic response
PMCID:3655407
PMID: 20878462
ISSN: 1573-7217
CID: 114178

Androgen receptor coactivator p44/Mep50 in breast cancer growth and invasion

Peng, Yi; Li, Yirong; Gellert, Lan Lin; Zou, Xuanyi; Wang, Jun; Singh, Baljit; Xu, Ruliang; Chiriboga, Luis; Daniels, Garrett; Pan, Ruimin; Zhang, David Y; Garabedian, Michael J; Schneider, Robert J; Wang, Zhengxin; Lee, Peng
Hormones and their receptors play an important role in the development and progression of breast carcinoma. Although the primary focus has been on oestrogen and oestrogen receptor (ER), androgen, androgen receptor (AR) and its coactivator(s) have been implicated in tumorigenesis of breast carcinoma and warrant further investigation. AR coactivator p44/Mep50 is identified as a subunit of methylosome complex and lately characterized as an AR coactivator that enhances AR mediated transcription activity in a ligand dependent manner. In prostate cancer, p44 is expressed in the nucleus of benign epithelia and translocated into the cytoplasm in cancer cells. Furthermore, nuclear expression of p44 inhibits prostate cancer growth. In this report, we examined the expression and function of p44 in breast cancer. In addition to being an AR coactivator, p44 also functions as an ER coactivator. In contrast to findings in prostate cancer, the expression of p44 shows strong cytoplasmic expression in morphologically normal terminal ductal lobular units, while nuclear p44 is observed in both ductal carcinoma in situ and invasive carcinoma. Further, overexpression of nuclear-localized p44 stimulates proliferation and invasion in MCF7 breast cancer cells in the presence of oestrogen and the process is ERalpha dependent. These findings strongly suggest that p44 plays a role in mediating the effects of hormones during tumorigenesis in breast
PMCID:3822728
PMID: 19840198
ISSN: 1582-4934
CID: 138376

Low-dose radiation augments vasculogenesis signaling through HIF-1-dependent and -independent SDF-1 induction

Lerman, Oren Z; Greives, Matthew R; Singh, Sunil P; Thanik, Vishal D; Chang, Christopher C; Seiser, Natalie; Brown, Daniel J; Knobel, Denis; Schneider, Robert J; Formenti, Silvia C; Saadeh, Pierre B; Levine, Jamie P
The inflammatory response to ionizing radiation (IR) includes a proangiogenic effect that could be counterproductive in cancer but can be exploited for treating impaired wound healing. We demonstrate for the first time that IR stimulates hypoxia-inducible factor-1alpha (HIF-1alpha) up-regulation in endothelial cells (ECs), a HIF-1alpha-independent up-regulation of stromal cell-derived factor-1 (SDF-1), as well as endothelial migration, all of which are essential for angiogenesis. 5 Gray IR-induced EC HIF-1alpha and SDF-1 expression was greater when combined with hypoxia suggesting an additive effect. While small interfering RNA silencing of HIF-1alpha mRNA and abolition of HIF-1alpha protein induction down-regulated SDF-1 induction by hypoxia alone, it had little effect on SDF-1 induction by IR, demonstrating an independent pathway. SDF-1-mediated EC migration in hypoxic and/or radiation-treated media showed IR induced strong SDF-1-dependent migration of ECs, augmented by hypoxia. IR activates a novel pathway stimulating EC migration directly through the expression of SDF-1 independent of HIF-1alpha induction. These observations might be exploited for stimulation of wound healing or controlling tumor angiogenesis
PMID: 20631377
ISSN: 1528-0020
CID: 138185

High levels of Hsp90 cochaperone p23 promote tumor progression and poor prognosis in breast cancer by increasing lymph node metastases and drug resistance

Simpson, Natalie E; Lambert, W Marcus; Watkins, Renecia; Giashuddin, Shah; Huang, S Joseph; Oxelmark, Ellinor; Arju, Rezina; Hochman, Tsivia; Goldberg, Judith D; Schneider, Robert J; Reiz, Luiz Fernando Lima; Soares, Fernando Augusto; Logan, Susan K; Garabedian, Michael J
p23 is a heat shock protein 90 (Hsp90) cochaperone located in both the cytoplasm and nucleus that stabilizes unliganded steroid receptors, controls the catalytic activity of certain kinases, regulates protein-DNA dynamics, and is upregulated in several cancers. We had previously shown that p23-overexpressing MCF-7 cells (MCF-7+p23) exhibit increased invasion without affecting the estrogen-dependent proliferative response, which suggests that p23 differentially regulates genes controlling processes linked to breast tumor metastasis. To gain a comprehensive view of the effects of p23 on estrogen receptor (ER)-dependent and -independent gene expression, we profiled mRNA expression from control versus MCF-7+p23 cells in the absence and presence of estrogen. A number of p23-sensitive target genes involved in metastasis and drug resistance were identified. Most striking is that many of these genes are also misregulated in invasive breast cancers, including PMP22, ABCC3, AGR2, Sox3, TM4SF1, and p8 (NUPR1). Upregulation of the ATP-dependent transporter ABCC3 by p23 conferred resistance to the chemotherapeutic agents etoposide and doxorubicin in MCF-7+p23 cells. MCF-7+p23 cells also displayed higher levels of activated Akt and an expanded phosphoproteome relative to control cells, suggesting that elevated p23 also enhances cytoplasmic signaling pathways. For breast cancer patients, tumor stage together with high cytoplasmic p23 expression more accurately predicted disease recurrence and mortality than did stage alone. High nuclear p23 was found to be associated with high cytoplasmic p23, therefore both may promote tumor progression and poor prognosis by increasing metastatic potential and drug resistance in breast cancer patients
PMCID:3007122
PMID: 20847343
ISSN: 1538-7445
CID: 114177

Five-year Results of Preoperative Paclitaxel with Concurrent Radiation Therapy in Locally Advanced Breast Cancer: Pathological Response Predicts for Survival [Meeting Abstract]

Schneider, R. J.; Formenti, S. C.; Chakravarthy, A.; Adams, S.; Spicer, D.; Lymberis, S.; Goldberg, J. D.; Pietenpol, J. A.
ISI:000282731700468
ISSN: 0360-3016
CID: 114016

Inflammatory Breast Cancer Radio-resistance and its Cancer Stem Cell Population are Oppositely Controlled by Translation Factor elF4G [Meeting Abstract]

Connolly, E. P.; Silvera, D.; Badura, M. L.; Braunstein, S. E.; Formenti, S. C.; Schneider, R. J.
ISI:000282731700474
ISSN: 0360-3016
CID: 114017