Multiple functions of the viral signal peptide(p14) in MMTV-associated breast cancer

In 2015 the World Health Organization reported 571,000 deaths from breast cancer worldwide. According to the American Cancer Society, 252,710 new cases of invasive breast cancer and 40,610 breast cancer deaths were expected to occur among USA women in 2017.

Mouse Mammary Tumor Virus (MMTV) is a Beta-retrovirus that causes mammary carcinoma and lymphoma in mice. An increasing body of evidence in recent years supports the involvement of MMTV in over 30% of human sporadic breast cancers.

We have identified the signal peptide of the envelope precursor protein of MMTV (MMTV-p14, or p14 for short) as a novel target for immune therapy of MMTV-associated breast cancer, based on the following characteristics:

1) It is expressed on the cell surface, as well as in nucleoli of murine lymphomas, mammary carcinomas and human breast cancer cells that contain (or ectopically express) MMTV sequences.

2) p14 is immunogenic, insofar as injection of the purified molecule into mice (using different adjuvants) induces specific antibody and T-cell mediated responses. We have exploited this trait for preventive vaccination against murine tumors that harbor MMTV.

3) Monoclonal anti-p14 antibodies as well as T-cells, isolated from mice primed and challenged with p14, were successfully used in in vivo immune therapy of MMTV-bearing murine tumors.

4) Interestingly, p14 has been found in sera of syngeneic mice challenged with murine mammary carcinoma and lymphoma cells that contain MMTV, suggesting shedding of this 98-amino acid protein (or peptides thereof) as a putative immune evasion mechanism.

5) Being a phosphoprotein, p14 functions, either in an oncogenic or anti-oncogenic capacity in vivo, depending on its phosphorylation status.

6) ) Using our anti-p14 antibodies in over 52 cases of breast cancer in Australian women, immunohistochemistry of FFPE slides demonstrated positivity in 22 of these samples. In addition, 33 of the 52 cases were also analysed in Italy using the same antibodies (but their reagents). 29 of these samples demonstrated identical findings (either negative or positive). Interestingly, positive reactions were also apparent in few patients with benign hyperplasia, that subsequently developed into p14-positive breast cancer (Lawson J et al. Frontiers Oncology, 2018).

In conclusion , we have at our disposal a unique set of mutant p14s that allow to ask mechanistic questions and define pathways specific to this multifunctional signal peptide, in an effort to impair its oncogenic capacity and/or enhance its anti-oncogenic capability.

Taken together, the above findings constitute a novel strategy towards preventive vaccination, detection and treatment of MMTV-associated breast cancers based on p14 (signal peptide) targeting.