Reduced expression of semaphorin 4D and plexin-B in breast cancer is associated with poorer prognosis and the potential linkage with oestrogen receptor

Abstract

Abstract. Involvement of semaphorin 4D (Sema4D) and the receptor proteins of the plexins B family (plexin-B1, -B2 and -B3) in solid tumours suggests they play a role in breast cancer. In the present study, the expression of Sema4D and plexin-Bs was examined in a breast cancer cohort. The expression of Sema4D and plexin-Bs was examined in 147 tumours together with 22 normal mammary tissues using quantitative PCR along with clinicopathological patient data, as well as in MCF-7 and MDA-MB-231 cell lines treated with selective oestrogen receptor modulators (SERMs). The expression of Sema4D, plexin-B1 and -B2 was markedly reduced in tumours with local recurrence, compared to the patients that remained disease-free. The reduced Sema4D expression was associated with poorer disease-free survival (median, 111.6 months, 95% CI, 96.5-126.7), compared to the patients with a higher expression (median, 144.0 months; 95% CI, p=0.033). A reduced expression of plexin-B1 was observed in tumours with poorer differentiation and was associated with poorer overall and disease-free survival. No similar association was identified in relation to plexin-B2 and -B3. A higher expression of Sema4D and plexin-B1 was observed in the ERα-positive tumours compared to the ERα-negative tumours. The expression of these molecules was largely regulated in breast cancer cells exposed to SERMs. A decreased expression of Sema4D, plexin-B1 and -B2 was associated with local recurrence and poor prognosis. Response to SERMs indicated potential perspectives of these molecules in clinical assessment and management of diseases. IntroductionBreast cancer is a heterogeneous disease influenced by genetic and environmental factors (1). Tumour metastasis is regulated by a set of non-randomized events, starting from loss of cancer cells adhesion at the primary site, local invasion, intravasation, survival in circulation, extravasation and colonisation at distant sites. The nervous and vascular system share several anatomical and developmental similarities as these systems are combined in neurovascular bundles and in peripheral tissues. Notably, these shared developmental links also assist scientists to speculate the involvement of certain molecules controlling growth and migration of nerves in cancer cell proliferation, differentiation and dissemination (2,3). Apart from acting as axonal guidance cues, the involvement of semaphorins and plexins in altering the cytoskeleton, organization of actin filaments and microtubule networks in non-neural systems has also been observed (4,5).Semaphorins are classified as secreted, transmembrane or glycosylphosphatidylinositol-linked proteins containing a phylogenetically conserved extracellular 'sema' domain. These molecules are further delineated into eight classes, of which classes 3-7 are present in vertebrates (6). Plexins are transmembrane protein receptors for semaphorins grouped further under A to D categories. Previously, the two families were initially identified as axon guidance cues in the nervous system and were la...

Rnd3-induced cell rounding requires interaction with Plexin-B2

“…It is plausible that plexin-B2 brings Rnd3 and p190RhoGAP together to enhance Rnd3-induced rounding. The role of plexin-B2 as a target for Rnd3 signalling could explain the apparently opposing effects of plexin-B2 in cancer cell invasion and cancer progression: in some cancer types such as breast cancer, both Rnd3 and plexin-B2 appear to inhibit hallmarks of tumorigenesis (Malik et al, 2015; Zhu et al, 2014), whereas in gliomas they promote tumour progression (Clarke et al, 2015; Le et al, 2015). …”

The combined expression of Semaphorin4D and PlexinB1 predicts disease recurrence in colorectal cancer

“…On the other hand, it was reported that the decreased expression of Sema4D and PlexinB1 was associated with local recurrence and poor prognosis in breast cancer [ 10 ]. Although, the expression of Sema4D and PlexinB1 have been investigated in some solid malignancies, the correlation between the expression of these factors and the prognosis of patients with malignant tumors remains controversial.…”

“…Recently, the role of Sema4D, via interaction with PlexinB1, in activities such as tumor angiogenesis and invasive growth have been discussed in relation to various types of tumors [ 8 – 10 ]. Thus, in the present study we investigated the expression of Sema4D and PlexinB1 in CRC tissue specimens and assessed their association with various clinicopathological factors.…”

Role of Plexin B1 in a Breast Cancer Cohort of Pakistani Patients and its Contribution Towards Cancer Metastasis as Indicated by an In Vitro Model

“…Extraction of RNA and synthesis of cDNA. RNA was isolated from both tumor and control tissues using TRIzol ® (Invitrogen, Carlsbad, CA, USA) as mentioned earlier (9). After extraction, RNA was dissolved in diethyl pyrocarbonate (DEPC)-treated autoclaved water and stored at −80˚C until further use.…”