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Overview of Prostate Cancer

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With over 160,000 new cases each year in the United States, prostate cancer (PCa) is the second leading cause of cancer-related death in men1. A complex and biologically heterogenous disease, most patients will benefit from not having treatment, while patients with high risk PCa are treated aggressively by either prostatectomy, radiation and/or androgen deprivation therapies (ADT). Ultimately even if initial treatment is successful there is an inevitable progression to castrate resistant disease (CPRC). One of the biggest challenges in treating PCa is accurately identifying patients who are either low or high risk.

There are three signaling pathways that are most commonly altered in PCa: the androgen receptor (AR) pathway, the PI3K pathway and rearrangements that make the ETS transcription factor family under the control of TMPRSS22.

AR signaling plays a key role in not only the normal growth and development of the prostate but also in prostate carcinogenesis and progression to CPRC3. In the absence of a ligand, the AR is associated with heat shock proteins in the cytoplasm. Both testosterone and dihydrotestosterone can bind to and activate AR resulting in the dimerization of AR and its translocation in to the nucleus. Once inside, AR binds to androgen response elements and with the help of coregulators either enhance or repress gene expression2. While almost 200 coregulators have been identified, mounting evidence suggests that prostate cancer is associated with overexpression of specific AR coregulators that may drive disease progression. For example, SRC1 expression is associated with a more aggressive form of PCa and is in increased in 50% of androgen-dependent prostate cancer and 63% in CPRC54.

The fusion of TMPRSS2-ERG is the most common chromosomal rearrangement in PCa occurring in 40% – 60% of patients. TMPRSS2-ERG fusions are thought to be an early event in PCa playing a key role in the initiation of cancer. TMPRSS2 is an androgen response promoter and places ERG under the control of AR signaling. The overexpression of ERG contributes to oncogenesis by the upregulation of MYC, EZH2 and SOX9 among others while repressing the tumor suppressor gene NKX3.1.

Activation of phosphoinsositidine-3-kinase (PI3K) occurs in 50% of PCa and is thought to be key in initiating the development of CPRC4. Activation of PI3K often occurs through deactivation of PTEN, which is a phosphatase that is known to deregulate the PI3K pathway and is either deleted or mutated in a majority of PCa5. The activated PI3K/AKT pathway can compensate the loss of AR signaling by increasing the expression of a several pro-proliferative factors including EGR1, c-JUN and EZH2. Because of this the combination of ADT with PI3K pathway inhibitors may be a more effective way of treating PCa than ADT alone.

 

 

Detection of human BAD (red) in FFPE prostate carcinoma by IHC.

Detection of human BAD (red) in FFPE prostate carcinoma by IHC.  Antibody: Rabbit anti-BAD (IHC-00677). Secondary: DyLight® 594-conjugated goat anti-rabbit IgG (A120-201D4). Counterstain: DAPI (blue).

Detection of human Matrin 3 in FFPE prostate carcinoma by IHC

Detection of human Matrin 3 in FFPE prostate carcinoma by IHC.  Antibody: Rabbit anti-Matrin 3 (IHC-00081).  Secondary: HRP-conjugated goat anti-rabbit IgG (A120-501P).  Substrate: DAB.

Detection of human ABCB9 (red) in FFPE prostate carcinoma by IHC-IF

Detection of human ABCB9 (red) in FFPE prostate carcinoma by IHC-IF. Antibody: Rabbit anti-ABCB9 (IHC-00398). Secondary: DyLight® 594-conjugated goat anti-rabbit IgG (A120-201D4). Counterstain: DAPI (blue).

 

Below is the current list of Bethyl antibodies involved in prostate cancer:

 

References

1. Janiczek M, Syzlberg L, Kasperska A, Kowalewski A, Parol M, Antosik P, Radecka B, Marszalek A. 2017. Immunotherapy as a promising treatment for prostate cancer: A systematic review. J Immunol Res. 4861570.

2. Dehm SM, Tindall DJ. 2006. Molecular regulation of androgen action in prostate cancer. J Cell Biochem. 99(2:)333-344.

3. Gregory CW, He B, Johnson RT, Ford OH, Mohler JL, French FS, Wilson EM. 2001. A mechanism for androgen receptor-mediated prostate cancer recurrence after androgen deprivation therapy. Cancer Research. 61(11):4315-4319.

4. Shtivelman E, Beer TM, Evans CP. 2014. Molecular pathways and targets in prostate cancer. Oncotarget. 5(17):7217-7259.

5. Lonergan PE, Tindall DJ. 2011. Androgen receptor signaling in prostate cancer development and progression. J Carcinog. 10(20).

6. Mulholland DJ, Tran LM, Li Y, Cai H, Morim A, Wang S, Plaisier S, Garraway IP, Huang J, Graeber TG, Hong W. 2011. Cell autonomous role of PTEN in regulation castration-resistant prostate cancer growth. Cancer Cell. 19(6):792-804.

7. Dahia PL. 2000. PTEN, a unique tumor suppressor gene. Endocr Relat Cancer. 7(2):115-129