Faculty Bibliography

Estrogen receptors (ER) play important roles in the development and progression of breast and ovarian cancers. ERs mediate transcriptional regulation through interaction with cofactors and binding to response elements within the regulatory elements of target genes. Here, we examined the expression and function of TBLR1/TBL1XR1, a core component of NCoR (nuclear receptor corepressor) and SMRT (silencing mediator of retinoic acid and thyroid receptor) corepressor complexes, in breast and ovarian cancers. We found that although TBLR1 is present in both the nucleus and cytoplasm of normal and neoplastic breast and ovarian cells, it is expressed at significantly higher levels in the nucleus of malignant breast and ovarian cells compared to benign cells. TBLR1 functions as an ER corepressor to inhibit ER-mediated transcriptional activation in both breast and ovarian cell lines, but it has no effect on androgen receptor (AR) mediated transcriptional activation in these cells. Furthermore, ectopic expression of nuclear TBLR1 in breast and ovarian cancer cells stimulates cell proliferation. The increased cell proliferation by nuclear TBLR1 is through both ER-independent and ER-dependent mechanisms as evidenced by increased growth in hormone-free medium and estrogen medium, as well as reduced growth with ER knockdown by siRNA. Nuclear TBLR1 overexpression also increased migration and invasion in both breast and ovarian cancer cells. Determining the functional relationship between TBLR1 and ER may provide insights to develop novel treatment strategies and improve response to hormonal therapy in breast and ovarian cancers.

Squamous cell carcinoma (SCC) and keratoacanthoma (KA; SCC/KA) research has been hampered mainly by our lack of understanding the underlying genetic and epigenetic alterations associated with SCC/KA development, as well as the lack of animal models that faithfully recapitulate histopathologic features of human SCC/KA. Here, we show that TPL2 overexpression induced both cell transformation in immortalized human keratinocytes and SCC and KA-like cutaneous SCC (cSCC) development in mice. Mechanistically, activation of TPL2 downstream signaling pathways such as MEK/ERK MAPK, mTOR, NF-kappaB, and p38 MAPK leads to TPL2-mediated cell transformation in immortalized human keratinocytes and tumorigenesis in mice. Most importantly, TPL2 overexpression is required for iTPL2 TG-driven SCC and KA-like cSCC tumor maintenance, validating TPL2 as a possible drug target for the treatment of SCC/KA. Finally, we verified that TPL2 is overexpressed in human cutaneous metastatic SCC and KA clinical specimens compared with normal skin. Taken together, our results establish TPL2 as an oncogenic driver in SCC/KA development. Cancer Res; 76(22); 1-11. (c)2016 AACR.

Significant differences, including epidemiologic, clinical, pathologic and genetic, exist between Asian and Caucasian prostate cancer. Detailed pathologic data are, however, scarce. We studied in detail and compared the pathological features of prostate cancer in radical prostatectomy specimens in 228 patients (117 Japan, 111 US). Japanese prostate cancer had a higher Gleason grade group (mean 2.67 vs. 2.42 US, P < 0.05), but lower pathological stage (72 % pT2 and 28 % pT3 vs 55 % pT2 and 45 % pT3 US, P < 0.05). Japanese cancer showed significantly more tumor foci (3.8 vs 2.9 US, P < 0.05), and higher incidence of bilateral significant disease (81.3 % vs. 66.7 % US, P < 0.05). The dominant tumor nodules in Japanese cases had higher Gleason grade group (mean 2.73 vs. 2.40 US, P < 0.05). The incidence of intraductal carcinoma was significantly higher in Japanese patients (35.3 % vs. 12.6 % US, P < 0.01), which was independent of Gleason score (7: 30.9 % Japan vs 11.8 % US, P < 0.01; >/= 8: 87.5 % Japan vs 28.6 % US, P < 0.01) and tumor stage (pT2: 24.1 % Japan vs 6.6 % US, P < 0.01; pT3: 62.9 % Japan vs 20 % US, P < 0.01). These findings demonstrate distinct pathological features in prostate cancer between Japanese and Caucasian patients, and may have important diagnostic and therapeutic implications.

Treatment protocols for breast cancer depend predominantly on receptor status with respect to estrogen (estrogen receptor alpha), progesterone (progesterone receptor) and human epidermal growth factor [human epidermal growth factor receptor 2 (HER2)]. The presence of one or more of these receptors suggests that a treatment targeting these pathways might be effective, while the absence of, or in the case of HER2, lack of overexpression of, all of these receptors, termed triple negative breast cancer (TNBC), indicates a need for the more toxic chemotherapy. In an effort to develop targeted therapies for TNBC, it will be necessary to differentiate among specific TNBC subtypes. The subset of TNBC that expresses androgen receptor (AR) has been determined to express genes consistent with a luminal subtype and therefore may be amenable to therapies targeting either AR, itself, or other pathways typical of a luminal subtype. Recent investigations of the AR signal pathway within breast cancer lead to AR as a significant target for breast cancer therapy with several clinical trials currently in progress. The subclass of TNBC that lacks AR, which we have termed quadruple negative breast cancer (QNBC) currently lacks a defined targetable pathway. Unlike AR-positive TNBC, QNBC predominantly exhibits a basal-like molecular subtype. Several subtypes and related pathway proteins are preferentially expressed in QNBC that may serve as effective targets for treatment, such as ACSL4, SKP2 and EGFR. ACSL4 expression has been demonstrated to be inversely correlated with expression of hormone/growth factor receptors and may thus serve as a biomarker for QNBC as well as a target for therapy. In the following review we summarize some of the current efforts to develop alternatives to chemotherapy for TNBC and QNBC.

The current substage classification of pT2 prostate cancer (AJCC, 7th edition, 2010) into pT2a (unilateral tumors <1/2 of lobe), pT2b (unilateral tumors >/=1/2 of lobe) and pT2c (bilateral tumors) is of questionable relevance. Many studies show no difference in prognosis between substages, and incidence of pT2b prostate cancer is low. Other classification systems have been proposed based on tumor volume, as measured by dominant nodule size or tumor percentage. We characterized pT2b tumors and assessed utility of current pT2 substaging in predicting biochemical recurrence-free survival after radical prostatectomy and compared with different substaging methods based on tumor volume. Patients with pT2 tumors were selected among patients who underwent radical prostatectomy from 1998 to 2008. Dominant nodule size was dichotomized as <1.6 cm vs. >/=1.6 cm. Tumor percentage was dichotomized as 25%. Kaplan-Meier analysis and multivariate Cox proportional hazard regression models were used to evaluate pathological parameters predictive of biochemical recurrence-free survival. 785 patients met criteria, of which 145 (18.5%) were pT2a, 15 (1.9%) were pT2b and 625 (79.6%) were pT2c. The pT2 substages were not significant predictors of biochemical recurrence-free survival on univariate or multivariate analysis. In a multivariate model, tumor percentage>25% (p=0.002) was associated with decreased biochemical recurrence-free survival. In patients with stage pT2 prostate cancer, the current substaging method lacks predictive value for biochemical recurrence-free survival after accounting for other pathologic and clinical predictors. However, tumor percentage (25%) is a promising approach to substaging of pT2 prostate cancer.

Renal cell carcinomas comprise a heterogeneous group of tumours with diverse clinicopathological and molecular characteristics as well as therapeutic options. Accurate diagnosis and classification are critical for patient management and prognosis prediction. They have traditionally been classified according to histopathological features. Recent advances in high throughput technologies, including next generation sequencing, have enabled us to search genome-wide for genomic, transcriptomic and proteomic changes in large number of renal cancer specimens. Studies have demonstrated that different histological subtypes harbour unique genomic and epigenetic alterations and gene expression and protein profile that can be integrated with clinicopathological features for diagnosis, classification, prognosis and individualized treatment and "n-of-1" trials. This review will discuss the immunoprofiles of major renal cell carcinoma subtypes, immunohistochemical markers that are commonly used in clinical laboratories, and recent genomic and epigenetic discoveries in renal cell carcinomas

BACKGROUND: The human papilloma virus (HPV) is a carcinogen known for its strong association with cervical cancers and cervical lesions. It is also known to be associated with a variety of squamous cell carcinomas in other areas, such as the penis, vulva, anus and head and neck. However, the association with urothelial carcinoma remains controversial. Here, we report a case of urothelial carcinoma with squamous differentiation associated with HPV-6/HPV-11. CASE PRESENTATION: This is a case of a 70 year old man who presented with nocturia and pressure during urination. During the TURP procedure for what was clinically thought to be benign prostate hyperplasia with pathologic diagnosis as prostate carcinoma, a 2 cm papillary mass was found in the distal penile urethra. The papillary mass was found to be a high grade urothelial carcinoma positive for GATA 3 expression, with focal areas of squamous differentiation. The areas with squamous differentiation demonstrated koilocytic differentiation, which were positive for strong p16 expression. The tumor was found to harbor low risk HPV 6/11 by in situ hybridization. CONCLUSIONS: This study case demonstrates HPV infection with a low risk subtype (HPV 6/11) associated with an urothelial carcinoma with squamous differentiation and condylomatous features.