Stathmin expression associates with vascular and immune responses in aggressive breast cancer subgroups

Abstract

Studies indicate that stathmin expression associates with PI3K activation in breast cancer, suggesting stathmin as a marker for targetable patient subgroups. Here we assessed stathmin in relation to tumour proliferation, vascular and immune responses, BRCA1 germline status, basal-like differentiation, clinico-pathologic features, and survival. Immunohistochemical staining was performed on breast cancers from two series (cohort 1, n = 187; cohort 2, n = 198), and mass spectrometry data from 24 cases and 12 breast cancer cell lines was examined for proteomic profiles. Open databases were also explored (TCGA, METABRIC, Oslo2 Landscape cohort, Cancer Cell Line Encyclopedia). High stathmin expression associated with tumour proliferation, p53 status, basal-like differentiation, BRCA1 genotype, and high-grade histology. These patterns were confirmed using mRNA data. Stathmin mRNA further associated with tumour angiogenesis, immune responses and reduced survival. By logistic regression, stathmin protein independently predicted a BRCA1 genotype (OR 10.0, p = 0.015) among ER negative tumours. Cell line analysis (Connectivity Map) implied PI3K inhibition in tumours with high stathmin. Altogether, our findings indicate that stathmin might be involved in the regulation of tumour angiogenesis and immune responses in breast cancer, in addition to tumour proliferation. Cell data point to potential effects of PI3K inhibition in tumours with high stathmin expression.Breast cancer is a heterogeneous disease with different molecular subtypes 1,2 . Among these, the basal-like category represents 10-15% of all cases. Most of the basal-like tumours are triple negative (ER−/PR−/HER2−), with high histological grade and usually a more aggressive clinical behaviour. Importantly, basal-like and triple negative breast cancers are also heterogeneous 3-5 , and current studies explore novel treatment targets and improved markers for these breast cancer subtypes. Notably, there is a strong association between cases arising in heterozygotes for pathogenic BRCA1 variants and a basal-like phenotype 6 . Henceforth, this genotype will be referred to as BRCA1 positive.Stathmin is a microtubule destabilizing protein important for the construction and function of the mitotic spindle 7,8 . Active, non-phosphorylated stathmin depolymerizes microtubules during interphase and late mitosis 8,9 . Tight regulation of stathmin function through phosphorylation, and de-phosphorylation is necessary for optimal function of the mitotic spindle and orderly progression through the cell cycle 9-11 . In addition to its role in mitosis, stathmin is involved in the regulation of other cellular processes such as epithelial polarity, apoptosis, and cell motility 12-14 . Further, Segatto and colleagues recently demonstrated that stathmin is required for ∆16HER2-driven early breast cancer development in mice 14 .In breast cancer, high stathmin levels are associated with aggressive features 15-17 and reduced survival 17-20 , and overexpression is reported in a variety of other...

Stathmin dynamics modulate the activity of eribulin in breast cancer cells

“…Some studies show that the affinity of stathmin for tubulin is increased in the presence of microtubule destabilizers, vinblastine or vinflunine, suggesting that stathmin modulates the activity of microtubule-targeting agents. 31,32 Since abnormally high levels of stathmin are associated with human malignancies and correlate with poor prognosis of breast cancer, [12][13][14] eribulin may effectively inhibit proliferation of stathmin-overexpressing cancer cells. Also, a combination of PTX and stathmin knockdown inhibits growth and promotes apoptosis of nasopharyngeal, 33 gastric, 34 and endometrial 35 carcinoma cells.…”

“…[7][8][9][10][11] High stathmin expression by breast cancer cells may be associated with aggressive characteristics and increased mortality. [12][13][14] Breast cancer cell lines overexpressing stathmin show reduced sensitivity to the microtubule-targeting drugs paclitaxel and vinca alkaloids,however, the combination of stathmin knockdown and treatment with these drugs exerts stronger antiproliferative effects. Furthermore, Meng et al 15 suggested that low expression of stathmin predicts high sensitivity to docetaxel-containing chemotherapy regimens.…”

PRSS2 stimulates tumor growth by remodeling the TME via repression of Tsp1

“…Two independent breast cancer series were immunohistochemically stained for PRSS2 protein. Series 1 is a population-based series of 544 primary breast carcinomas from the period 1996-2003, and Series 2 is a case-control series of 202 primary breast carcinomas (53 BRCA1 , 45 BRCA2 and 104 BRCA non-mutated) from the period 1986-2005, as previously described 38, 39 . Twenty-six cases from Series 1 and 30 cases from Series 2 were excluded due to technical inadequate material, leaving 518 and 172 cases for evaluation of PRSS2 staining.…”

TRP Channels Interactome as a Novel Therapeutic Target in Breast Cancer

“…Stathmin1 is a protein which active or non-phosphorylated form mediates depolymerization of microtubules in late mitosis ( 115 ). Interestingly, it has been reported that tumors with high levels of this protein show enhanced proliferation, angiogenesis and immune response evasion, mainly in basal like subtypes of breast cancer ( 116 ). Moreover, increased expression of Stathmin1 correlates with poor prognosis for patients with breast cancer ( 117 ).…”