Aim: Breast cancer is the most prevalent malignant tumor among women. Human papillomavirus (HPV) has been detected in breast tumors since the 1990s, and beyond its oncogenic potential, therapy resistance driven by viral immune evasion in non-anogenital tumors, such as oropharyngeal cancers, highlights the need to investigate viral activity in breast tissues. Among high-risk HPV types, HPV16 is one of the most prevalent and exhibits the highest carcinogenic potential. Therefore, this study aimed to evaluate the expression of HPV16 oncogenes E5, E6, and E7 in breast tumors, as well as the modulation of the PI3K/AKT/mTOR signaling pathway associated with viral activity. Methods: A total of 92 breast cancer patients were included after Ethics Committee approval. Clinical data were obtained from medical records. RNA was extracted from formalin-fixed, paraffin-embedded tissues and reverse-transcribed into cDNA. Transcripts of HPV oncogenes (E5, E6, and E7), components of the PI3K/AKT/mTOR pathway, and regulatory genes (EGFR and PTEN) were quantified by RT-qPCR. Gene expression levels were calculated using the ΔCt method. Results: Forty-eight samples met RNA quality criteria and were included in the expression analysis. Among these, 77.08% showed expression of at least one viral oncogene, with E5 being the most frequently expressed. The PI3K/AKT/mTOR pathway was modulated in HPV-positive samples, with increased PI3K expression and decreased mTOR expression. Notably, the high expression of E5—associated with immune evasion—combined with reduced mTOR expression suggests that HPV16 status may influence therapeutic response in breast cancer patients. Conclusions: These findings reinforce the importance of further studies investigating HPV activity in breast tumors to better understand its biological and clinical impact.

Breast cancer is a heterogeneous disease influenced by genetic, hormonal, environmental, and biological factors. Among potential biological contributors, Human Papillomavirus (HPV) has attracted increasing attention due to its established oncogenic role in other malignancies. Although the association between HPV and breast cancer remains controversial, emerging evidence suggests that viral oncoproteins may modulate key components of the breast tumor microenvironment (TME). HPV oncoproteins E5, E6, and E7 have been associated with the regulation of inflammatory signaling, immune responses, extracellular matrix remodeling, and activation of oncogenic pathways, including JAK/STAT, PI3K/AKT/mTOR, and NF-κB. These alterations may promote chronic inflammation, immune evasion, angiogenesis, and tumor progression. This review discusses current evidence regarding the relationship between HPV infection and the breast TME, highlighting potential mechanisms through which the virus may influence breast cancer biology. While definitive evidence supporting a causal role of HPV in breast carcinogenesis is still lacking, available findings indicate that HPV may act as an important modulator of the breast tumor microenvironment, representing a promising area for future translational and therapeutic research.