Steroidhormoners rolle i kreftutvikling - et litteraturstudium

Sammenhengen mellom steroidhormoner og kreftutvikling har vært studert i flere tiår og det er velkjent at de kvinnelige kjønnshormonene østrogen og progesteron spiller viktige roller i utviklingen av hormonavhengige krefttyper som bryst-, ovarial- og livmorkreft. Likeledes er testosteron sin rolle i utviklingen av prostatakreft et felt som har blitt forsket, og fortsatt forskes, mye på. Hormonenes viktige rolle i kreftutviklingen har blitt bekreftet blant annet gjennom utviklingen av anti-østrogener som tamoxifen og toremifene, samt anti-androgener som cyproteron, som i dag anvendes i bekjempelsen av henholdsvis bryst- og prostatakreft. Tall fra 2012 innhentet av American Cancer Society viser at omtrent 35% av nye krefttilfeller faller inn under kategorien hormonrelaterte krefttyper, hvert år. Disse organenes vekst og utvikling er kontrollert av et eller flere steroidhormoner eller polypeptidhormoner. Det er gjort store framskritt i å forstå sammenhengen mellom steroidhormoner og kreft, mye takket være to viktige oppdagelser: (a) antall vev og celler som påvirkes av steroidhormoner har økt enormt, grunnet ny kunnskap som tillater påvisning av reseptorutrykk. I tillegg vet man nå at (b) effekten av steroidhormoner er langt bredere enn den klassiske kjernereseptormedierte effekten som lenge var antatt å være den eneste. Dette er et litteraturstudium som beskriver koblingen mellom steroidhormoner og kreftutvikling

High progesterone receptor expression in prostate cancer is associated with clinical failure

Background Prostate cancer is a highly heterogeneous disease and one of the leading causes of mortality in developed countries. Specific prognostic and predictive markers for prostate cancer patients are still lacking. A causal relationship between androgens and the development of prostate cancer is generally considered biologically plausible, but androgens are not the sole effector in the complexity of prostate carcinogenesis. The aim of this study was to evaluate the prognostic significance of progesterone receptor in tumor tissue of T1-3N0 prostate cancer patients undergoing prostatectomy. Methods Tissue microarrays from 535 patients with prostate cancer were constructed. Duplicate cores of tumor cells and tumor stromal tissue from each resected specimen were extracted. Immunohistochemistry was used to evaluate the in-situ expression of progesterone receptor. Results In univariate analyses, high tumor cell density (p = 0.006) and high tumor stromal cell density level (p = 0.045) of progesterone receptor were both significantly associated with tumor progression and clinical failure. In multivariate analysis, progesterone receptor expression in tumor cells was an independent negative prognostic factor for clinical failure (HR: 2.5, 95% CI: 1.2–5.2, p = 0.012). Conclusion High progesterone receptor density in tumor cells of the prostate cancer tumor is an independent negative prognostic factor for clinical failure

Progesterone receptors in prostate cancer: Progesterone receptor B is the isoform associated with disease progression

The role of steroid hormones in carcinogenesis of the prostate is to some extent unraveled thorough the effect of androgen deprivation therapy on prostate cancer (PCa) progression. Other members of the steroid hormone family, such as progesterone, are also implicated in PCa, but progesterone’s role remains undefined. This study aimed to examine the distribution of progesterone receptor isoforms (PGRA, PGRB) in PCa tissue and their association with clinical endpoints. This was conducted retrospectively by collecting radical prostatectomy specimens from 535 patients. Tissue was analyzed using tissue microarray, where representative tumor areas were carefully selected. Protein expression was evaluated through immunohistochemistry, in stromal and epithelial tissue. Associations between receptor expression and clinical data were considered using statistical survival analyses. Herein, we discovered a solely stromal PGRA- and a stromal and epithelial PGRB expression. Further, a high PGRB expression in tumor tissue was associated with an unfavorable prognosis in both univariate and multivariate analyses: Biochemical failure (HR: 2.0, 95% CI: 1.45–2.76, p < 0.001) and clinical failure (HR: 2.5, 95% CI: 1.29–4.85, p = 0.006). These findings are in agreement with our previous investigation on pan-PGR, indicating that the observed negative effect of PGR is represented by PGRB

Estrogen receptors α and β and aromatase as independent predictors for prostate cancer outcome

Androgens are considered important in normal prostate physiology and prostate cancer (PCa) pathogenesis. However, androgen-targeted treatment preventing PCa recurrence is still lacking. This indicates additional mediators contributing to cancer development. We sought to determine the prognostic significance of estrogen receptors, ERα and -β, and the aromatase enzyme in PCa. Tissue microarrays were created from 535 PCa patients treated with radical prostatectomy. Expression of ERα, ERβ and aromatase were evaluated using immunohistochemistry. Representative tumor epithelial (TE) and tumor stromal (TS) areas were investigated separately. Survival analyses were used to evaluate the markers correlation to PCa outcome. In univariate analyses, ERα in TS was associated with delayed time to clinical failure (CF) (p = 0.042) and PCa death (p = 0.019), while ERβ was associated with reduced time to biochemical failure (BF) (p = 0.002). Aromatase in TS and TE was associated with increased time to BF and CF respectively (p = 0.016, p = 0.046). Multivariate analyses supported these observations, indicating an independent prognostic impact of all markers. When stratifying the analysis according to different surgical centers the results were unchanged. In conclusion, significant prognostic roles of ERα, ERβ and aromatase were discovered in the in PCa specimens of our large multicenter cohort

A gender specific improved survival related to stromal miR-143 and miR-145 expression in non-small cell lung cancer

Micro RNAs (miRNA) are small non-coding RNAs that post-transcriptionally regulate gene expression. Dysregulation of miRNA cluster 143/145 has been reported in several malignancies, but their role in non-small cell lung cancer (NSCLC) remains elusive. This study investigates the prognostic impact of miR-143 and miR-145 in primary tumors and metastatic lymph nodes in NSCLC tissue. Tissue from 553 primary tumors and 143 matched metastatic lymph nodes were collected and tissue microarrays were constructed. In situ hybridization was used to evaluate miR-143 and miR-145 expression in tumor epithelial cells and stromal cells in the primary tumors and lymph nodes. In vivo data was supplemented with functional studies of cell lines in vitro to evaluate the role of miR-143 and miR-145 in NSCLC tumorigenesis. In our cohort, stromal miR-143 (S-miR-143) and miR-145 (S-miR-145) expression in primary tumor tissue were independent prognosticators of improved disease-specific survival (DSS) in female (S-miR-143, HR: 0.53, p = 0.019) and male patients (S-miR-145, HR: 0.58, p = 0.021), respectively. Interesting correlations between the miR cluster 143/145 and previously investigated steroid hormone receptors from the same cohort were identified, substantiating their gender dependent significance

Patient characteristics and clinicopathological variables as predictors for BF, CF and PCD in PCa patients (n = 535) (univariate analyses; log rank test), significant p-values in bold (threshold p ≤ 0.05).

<p>Patient characteristics and clinicopathological variables as predictors for BF, CF and PCD in PCa patients (n = 535) (univariate analyses; log rank test), significant p-values in bold (threshold p ≤ 0.05).</p

High and low progesterone receptor (PGR) protein density levels in human prostate cancer (PCa) tissue sections.

<p>Immunohistochemistry microscopic pictures of tissue micro array representing different expression of PGR staining in PCa sections A-B. (<b>A)</b> High density of PGR in tumor cells (TE), including magnification. <b>(B)</b> Low density of PGR in TE, including magnification. Original magnification x100 and x400.</p

High progesterone receptor (PGR) density level is associated with reduced clinical failure free survival (CFFS).

<p>Kaplan-Meier curves displaying proportion of prostate caner patients (n = 535) with CFFS according to high and low density level of progesterone receptor (PGR) in different cell types A-D. <b>(A)</b> Tumor stromal cells (TS), <b>(B)</b> tumor cells (TE), <b>(C)</b> TE and TS combined and <b>(D)</b> TE in patients with a high Gleason score (≥ 7). A high PGR density level is significantly associated with a reduction in CFFS. In both TE and TS, cut off was defined as the density level × 4^th quartile. A high score was defined as density level ≥ 0.75 in TE, and ≥ 1.75 in TS. Log-rank tests were used to assess the statistical significance between the survival curves of the model. Median follow-up time was 89 (range 6–188) months. A p-value < 0.05 was considered statistically significant.</p

Cox regression analysis (backwards stepwise model) summarizing significant independent prognostic factors for CF in PCa patients (n = 535), significant p-values in bold (threshold p ≤ 0.05).

<p>Cox regression analysis (backwards stepwise model) summarizing significant independent prognostic factors for CF in PCa patients (n = 535), significant p-values in bold (threshold p ≤ 0.05).</p