Chemotherapy induces ACE2 expression in breast cancer via the ROS-AKT-HIF-1α signaling pathway: a potential prognostic marker for breast cancer patients receiving chemotherapy.

BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system and a well-known functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The COVID-19 pandemic has brought ACE2 into the spotlight, and ACE2 expression in tumors and its relationship with SARS-COV-2 infection and prognosis of cancer patients have received extensive attention. However, the association between ACE2 expression and tumor therapy and prognosis, especially in breast cancer, remains ambiguous and requires further investigation. We have previously reported that ACE2 is elevated in drug-resistant breast cancer cells, but the exact function of ACE2 in drug resistance and progression of this malignant disease has not been explored. METHODS: The expression of ACE2 and HIF-1α in parental and drug-resistant breast cancer cells under normoxic and hypoxic conditions was analyzed by Western blot and qRT-PCR methods. The protein levels of ACE2 in plasma samples from breast cancer patients were examined by ELISA. The relationship between ACE2 expression and breast cancer treatment and prognosis was analyzed using clinical specimens and public databases. The reactive oxygen species (ROS) levels in breast cancer cells were measured by using a fluorescent probe. Small interfering RNAs (siRNAs) or lentivirus-mediated shRNA was used to silence ACE2 and HIF-1α expression in cellular models. The effect of ACE2 knockdown on drug resistance in breast cancer was determined by Cell Counting Kit 8 (CCK-8)-based assay, colony formation assay, apoptosis and EdU assay. RESULTS: ACE2 expression is relatively low in breast cancer cells, but increases rapidly and specifically after exposure to anticancer drugs, and remains high after resistance is acquired. Mechanistically, chemotherapeutic agents increase ACE2 expression in breast cancer cells by inducing intracellular ROS production, and increased ROS levels enhance AKT phosphorylation and subsequently increase HIF-1α expression, which in turn upregulates ACE2 expression. Although ACE2 levels in plasma and cancer tissues are lower in breast cancer patients compared with healthy controls, elevated ACE2 in patients after chemotherapy is a predictor of poor treatment response and an unfavorable prognostic factor for survival in breast cancer patients. CONCLUSION: ACE2 is a gene in breast cancer cells that responds rapidly to chemotherapeutic agents through the ROS-AKT-HIF-1α axis. Elevated ACE2 modulates the sensitivity of breast cancer cells to anticancer drugs by optimizing the balance of intracellular ROS. Moreover, increased ACE2 is not only a predictor of poor response to chemotherapy, but is also associated with a worse prognosis in breast cancer patients. Thus, our findings provide novel insights into the spatiotemporal differences in the function of ACE2 in the initiation and progression of breast cancer.

Estrogen and Androgen Receptor Inhibitors: Unexpected Allies in the Fight Against COVID-19.

TRANSLATIONAL RELEVANCE: No prophylactic treatments for COVID-19 have been clearly proven and found. In this pandemic context, cancer patients constitute a particularly fragile population that would benefit the best from such treatments, a present unmet need. TMPRSS2 is essential for COVID-19 replication cycle and it is under androgen control. Estrogen and androgen receptor dependent cues converge on TMPRSS2 regulation through different mechanisms of action that can be blocked by the use of hormonal therapies. We believe that there is enough body of evidence to foresee a prophylactic use of hormonal therapies against COVID-19 and this hypothesis can be easily tested on cohorts of breast and prostate cancer patients who follow those regimens. In case of pandemic, if the protective effect of hormonal therapies will be proven on cancer patients, the use of specific hormonal therapies could be extended to other oncological groups and to healthy individuals to decrease the overall risk of infection by SARS-CoV-2.Given the COVID-19 coronavirus emergency, a special focus is needed on the impact of this rapidly spreading viral infection on cancer patients. Androgen receptor (AR) signaling in the transmembrane protease serine 2 (TMPRSS2) regulation is emerging as an important determinant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) susceptibility. In our study, we analyzed AR and TMPRSS2 expression in 17,352 normal and 9,556 cancer tissues from public repositories and stratified data according to sex and age. The emerging picture is that some patient groups may be particularly susceptible to SARS-CoV-2 infection and may benefit from antiandrogen- or tamoxifen-based therapies. These findings are relevant to choose proper treatments in order to protect cancer patients from concomitant SARS-CoV-2 contagion and related symptoms and put forward the idea that hormonal therapies could be used as prophylactic agents against COVID-19.

Management of early breast cancer during the COVID-19 pandemic in Brazil.

PURPOSE: The COVID-19 pandemic has impacted early breast cancer (EBC) treatment worldwide. This study analyzed how Brazilian breast specialists are managing EBC. METHODS: An electronic survey was conducted with members of the Brazilian Society of Breast Cancer Specialists (SBM) between April 30 and May 11, 2020. Bivariate analysis was used to describe changes in how specialists managed EBC at the beginning and during the pandemic, according to breast cancer subtype and oncoplastic surgery. RESULTS: The response rate was 34.4% (503/1462 specialists). Most of the respondents (324; 64.4%) lived in a state capital city, were board-certified as breast specialists (395; 78.5%) and either worked in an academic institute or one associated with breast cancer treatment (390; 77.5%). The best response rate was from the southeast of the country (240; 47.7%) followed by the northeast (128; 25.4%). At the beginning of the pandemic, 43% changed their management approach. As the outbreak progressed, this proportion increased to 69.8% (p < 0.001). The southeast of the country (p = 0.005) and the state capital cities (p < 0.001) were associated with changes at the beginning of the pandemic, while being female (p = 0.001) was associated with changes during the pandemic. For hormone receptor-positive tumors with the best prognosis (Ki-67 < 20%), 47.9% and 17.7% of specialists would recommend neoadjuvant endocrine therapy for postmenopausal and premenopausal women, respectively. For tumors with poorer prognosis (Ki-67 > 30%), 34% and 10.9% would recommend it for postmenopausal and premenopausal women, respectively. Menopausal status significantly affected whether the specialists changed their approach (p < 0.00001). For tumors ≥ 1.0 cm, 42.9% of respondents would recommend neoadjuvant systemic therapy for triple-negative tumors and 39.6% for HER2 + tumors. Overall, 63.4% would recommend immediate total breast reconstruction, while only 3.4% would recommend autologous reconstruction. In breast-conserving surgery, 75% would recommend partial breast reconstruction; however, 54.1% would contraindicate mammoplasty. Furthermore, 84.9% of respondents would not recommend prophylactic mastectomy in cases of BRCA mutation. CONCLUSIONS: Important changes occurred in EBC treatment, particularly for hormone receptor-positive tumors, as the outbreak progressed in each region. Systematic monitoring could assure appropriate breast cancer treatment, mitigating the impact of the pandemic.