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Abstract
BackgroundThe introduction of cART has changed the morbidity and mortality patterns affecting HIV-infected (HIV+) individuals. The risk of breast cancer in HIV+ patients has now approached the general population risk. However, breast cancer has a more aggressive clinical course and poorer outcome in HIV+ patients than in general population, without correlation with the CD4 or virus particles count. These findings suggest a likely influence of HIV-1 proteins on breast cancer aggressiveness and progression. The HIV-1 matrix protein (p17) is expressed in different tissues and organs of successfully cART-treated patients and promotes migration of different cells. Variants of p17 (vp17s), characterized by mutations and amino acid insertions, differently from the prototype p17 (refp17), also promote B-cell proliferation and transformation.MethodsWound-healing assay, matrigel-based invasion assay, and anchorage-independent proliferation assay were employed to compare the biological activity exerted by refp17 and three different vp17s on the triple-negative human breast cancer cell line MDA-MB 231. Intracellular signaling was investigated by western blot analysis.ResultsMotility and invasiveness increased in cells treated with both refp17 and vp17s compared to untreated cells. The effects of the viral proteins were mediated by binding to the chemokine receptor CXCR2 and activation of the ERK1/2 signaling pathway. However, vp17s promoted MDA-MB 231 cell growth and proliferation in contrast to refp17-treated or not treated cells.ConclusionsIn the context of the emerging role of the microenvironment in promoting and supporting cancer cell growth and metastatic spreading, here we provide the first evidence that exogenous p17 may play a crucial role in sustaining breast cancer cell migration and invasiveness, whereas some p17 variants may also be involved in cancer cell growth and proliferation.
Highlights
The introduction of Combined antiretroviral therapy (cART) has changed the morbidity and mortality patterns affecting HIV-infected (HIV+) individuals
We have provided evidence that a p17 variant derived from a Ugandan Human immune deficiency virus type 1 (HIV-1) strain A1 (S75X) triggers an activation of the PI3K/Serine/threonine protein kinase (Akt) signaling pathway in B-cells, compared to a prototype p17 isolated from clone BH10 of clade B
Refp17 and its variants increase MDA-MB 231 cell migration The ability of refp17 and vp17s to promote the migratory activity of MDA-MB 231 cells was assessed by wound healing assay
Summary
The introduction of cART has changed the morbidity and mortality patterns affecting HIV-infected (HIV+) individuals. Breast cancer has a more aggressive clinical course and poorer outcome in HIV+ patients than in general population, without correlation with the CD4 or virus particles count These findings suggest a likely influence of HIV-1 proteins on breast cancer aggressiveness and progression. Recent studies have evidenced a more aggressive clinical course, poorer outcome and younger age at diagnosis of breast cancer in the HIV-1 setting compared to general population [15,16,17] These findings suggest a Caccuri et al Infectious Agents and Cancer (2017): likely influence of HIV-1 on breast cancer progression, the retrovirus does not show any capability to exert a direct tumorigenic effect on this cancer [15]
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