AKAP3 correlates with triple negative status and disease free survival in breast cancer

Looking for genes that are specifically expressed in cancer tissues and have a limited
expression in normal tissues is one of the most important targets of researchers in
the field of cancer treatment. Among these targets, CTAs could be a promising option
and there are a lot of researches in this field 1], 2], 7]–9]. In this study expression of AKAP3 were investigated in tumor, normal adjacent and
normal tissue of the breast in association with clinical features of the patients.

AKAP3 is classified as one of the members of scaffold proteins (AKAPs). They are a
family of about 50 scaffolding proteins which anchor protein kinase A (PKA) II and
other proteins including protein kinases, protein phosphatases and phosphodiesterases.
So they can specify intracellular locations and restrict the corresponding enzymatic
activities 10], 11]. As a result of multi-protein complexes which are formed by these anchoring proteins,
cAMP signaling is integrated with other pathways 5]. Such a compartmentalization represents the critical roles of AKAPs in cellular activities.
Accordingly subtle changes in the AKAPs related pathways or their components is an
explanation of the development of many diseases, especially cancer 12].

Triple negative breast cancer is still poorly characterized at the molecular level
and Lack of prognostic markers and selective targets of therapy make it the most aggressive
type of breast cancer which deserves more investigation 13], 14]. In the current study AKAP3 expression is deficient significantly in triple negative
tumors. CAMP-dependent protein kinase is usually present in tissues as a mixture of
type I and type II isozyme and changing their ratio involved in the oncogenic process.
The PKAII is mostly present in normal tissues, whereas its isoform PKAI which is not
related to AKAPs is expressed in malignant tissues 15]. Since AKAP3 is a scaffold for binding of PKAII, lack of AKAP3 expression which is
seen in this study may be due to the absence or decreased level of PKAII in malignant
tissues. Although this could be the reason of absence of AKAP3 expression in malignant
tissue, we still don’t know whether the hormone independence status in triple negative
tissues affects this status or not. If this protein have eligibility to use as prognostic
factor in triple negative patient require further investigation. Based on this study,
AKAP3 expression decreased significantly while tumors increased in size and stage.
This may be due to the association of PKAII with inhibition of mitogenic signaling
and cell growth 16]. Moreover, since PKA signaling with different AKAPs may direct cell toward proliferation
or death, AKAP3 may act as an inhibitor of proliferation signals 17]. But, further study need to decide about this suggestion because down regulated genes
are not always involved in inhibition of proliferation.

Based on the results, the patients with lack of AKAP3 in their normal adjacent tissues
represent the poorer outcome. The analysis between expression of this gene and different
treatment subtypes revealed no significant results which may show that the significant
differences in patient survival, found in this study, would be originated from the
difference in AKAP3 expression not therapy distribution between two groups of patients.
In the previous study by Sharma s et al., AKAP3 expression correlated with poor prognosis
in epithelial ovarian cancer 6], but its expression was not explored in normal adjacent tissue. Alteration in gene
expression of histologically normal adjacent tissue is a matter of debate. A number
of studies suggested that morphologically normal tissue adjacent to carcinomas has
not undergone significant gene expression changes when compared to normal tissue 18]. In contrast, some evidence suggests that these tissues represent modifications in
molecular level resembling tumor tissues 19]. These alterations can reveal the earliest changes leading to tumorigenesis or may
due to the effect of the tumor. In two studies in prostate cancer, microarray comparison
of tumor, normal adjacent and normal tissue revealed up- regulation of transcription
factors, signal transducers and growth regulatory genes in tumor and normal adjacent
but normal tissues 20], 21]. In 2006 Schneiders et al., suggested that the genetic profile of the normal adjacent
tissue may be associated with treatment failure in rectal cancer, suggesting the importance
of the tumor microenvironment in the development of recurrence of rectal tumors 22]. Since recurrence is a significant clinical problem for patients with cancer, having
the possibility of genetic assessment in normal material of patients in predicting
the recurrence is of great interest in medical research. More research on AKAP3 on
easily accessible tissues of the patients could help to decide whether it is possible
to use normal material of the patients to predict the outcome of the treatment.